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1
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Zhu CZ, Li GZ, Lyu HF, Lu YY, Li Y, Zhang XN. Modulation of autophagy by melatonin and its receptors: implications in brain disorders. Acta Pharmacol Sin 2025; 46:525-538. [PMID: 39448859 PMCID: PMC11845611 DOI: 10.1038/s41401-024-01398-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/17/2024] [Indexed: 10/26/2024]
Abstract
Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.
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Affiliation(s)
- Chen-Ze Zhu
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, 310058, China
| | - Gui-Zhi Li
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, China
| | - Hai-Feng Lyu
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, China
| | - Yang-Yang Lu
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, 310058, China
| | - Yue Li
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, 310058, China
| | - Xiang-Nan Zhang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, 310058, China.
- Jinhua Institute of Zhejiang University, Jinhua, 321299, China.
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2
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Tripathy S, Bhattamisra SK. Cellular signalling of melatonin and its role in metabolic disorders. Mol Biol Rep 2025; 52:193. [PMID: 39903334 DOI: 10.1007/s11033-025-10306-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/27/2025] [Indexed: 02/06/2025]
Abstract
Melatonin released from the pineal gland plays an important role in maintaining the light/dark cycle. Melatonin exerts its effects on various organs through receptor and nonreceptor pathways. Recently, the role of melatonin in various metabolic disorders has been investigated. This review focuses on the molecular pathways associated with melatonin and its role in metabolic disorders. In humans, melatonin acts through two G protein-coupled receptors (MT1 and MT2). Melatonin modulates insulin release, such as elevated insulin levels in the evening compared to morning hours, exerts cardioprotective effects through the cGMP pathway and nitric oxide production in endothelial cells, and controls oxidative stress and apoptosis in myocardial tissue. Melatonin through MT2 receptors increases lipolysis and thermogenesis, which have a positive effect on weight reduction in obese individuals. Currently, most drugs that target melatonin receptors are primarily used to treat neurological disorders. A detailed investigation to explore the role of melatonin and its signalling pathway in peripheral organs is essential to develop therapeutic molecules for managing metabolic disorders.
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Affiliation(s)
- Snehasis Tripathy
- IMT Pharmacy College, Sai Bihar, Gopalpur, Puri, Odisha, 752004, India
| | - Subrat Kumar Bhattamisra
- Department of Pharmacy, School of Health Science, Central University of South Bihar, Gaya, Bihar, 824236, India.
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3
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Cardenas-Padilla AJ, Jimenez-Trejo F, Cerbon M, Chavez-Garcia A, Cruz-Cano NB, Martinez-Torres M, Alcantar-Rodriguez A, Medrano A. Sperm melatonin receptors, seminal plasma melatonin and semen freezability in goats. Theriogenology 2024; 225:98-106. [PMID: 38801791 DOI: 10.1016/j.theriogenology.2024.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Goat bucks are seasonal breeders that show variation in sperm quality, endogenous melatonin (MLT), and presumably in the expression of MLT receptors on the sperm throughout the year, which may modify sperm freezability. The aim of this study was to determine whether sperm freezability is associated with (i) endogenous melatonin levels in seminal plasma and (ii) the expression of sperm plasma membrane melatonin receptors (MT1, MT2). To evaluate this, spermatozoa from seven Saanen goat bucks were cryopreserved throughout the year in Mexico using a standard freezing protocol. Seminal plasma MLT concentrations were determined by ELISA and the expression and localization of MT1 and MT2 were detected by immunocytochemistry and confirmed by western blotting. The recovery rate of progressive motility after thawing was higher in spring than autumn and winter; in contrast, the F pattern (CTC assay) was higher in winter than in the other seasons. A proportional increase in the AR pattern (CTC assay) was smaller in winter than in the other seasons and the proportion of sperm showing high plasma membrane fluidity was higher in spring than in summer and autumn. The seminal plasma MLT concentrations showed no significant interseasonal differences. The MT1 receptor was immunolocalised at the apical region of the sperm head, while MT2 was mainly localised in the neck. The relative expression of MLT receptors showed significant differences between summer and winter for all bands, except at 75 kDa of MT2. In conclusion, there was an association between the relative expression of MT1 and MT2 receptors throughout the year and sperm freezability in goat bucks in México. Post-thaw sperm quality is enhanced in semen samples collected during breeding season.
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Affiliation(s)
- Alberto J Cardenas-Padilla
- Laboratorio de Reproducción Animal, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, 54714, Estado de México, Mexico.
| | | | - Marco Cerbon
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico.
| | - Araceli Chavez-Garcia
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán, 04510, Ciudad de México, Mexico.
| | - Norma B Cruz-Cano
- Laboratorio de Biología de la Reproducción, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, 54090, Estado de México, Mexico.
| | - Martin Martinez-Torres
- Laboratorio de Biología de la Reproducción, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, 54090, Estado de México, Mexico.
| | - Alicia Alcantar-Rodriguez
- Laboratorio de Reproducción Animal, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, 54714, Estado de México, Mexico.
| | - Alfredo Medrano
- Laboratorio de Reproducción Animal, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, 54714, Estado de México, Mexico.
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4
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Bou‐Abdallah F, Fish J, Terashi G, Zhang Y, Kihara D, Arosio P. Unveiling the stochastic nature of human heteropolymer ferritin self-assembly mechanism. Protein Sci 2024; 33:e5104. [PMID: 38995055 PMCID: PMC11241160 DOI: 10.1002/pro.5104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/18/2024] [Accepted: 06/23/2024] [Indexed: 07/13/2024]
Abstract
Despite ferritin's critical role in regulating cellular and systemic iron levels, our understanding of the structure and assembly mechanism of isoferritins, discovered over eight decades ago, remains limited. Unveiling how the composition and molecular architecture of hetero-oligomeric ferritins confer distinct functionality to isoferritins is essential to understanding how the structural intricacies of H and L subunits influence their interactions with cellular machinery. In this study, ferritin heteropolymers with specific H to L subunit ratios were synthesized using a uniquely engineered plasmid design, followed by high-resolution cryo-electron microscopy analysis and deep learning-based amino acid modeling. Our structural examination revealed unique architectural features during the self-assembly mechanism of heteropolymer ferritins and demonstrated a significant preference for H-L heterodimer formation over H-H or L-L homodimers. Unexpectedly, while dimers seem essential building blocks in the protein self-assembly process, the overall mechanism of ferritin self-assembly is observed to proceed randomly through diverse pathways. The physiological significance of these findings is discussed including how ferritin microheterogeneity could represent a tissue-specific adaptation process that imparts distinctive tissue-specific functions to isoferritins.
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Affiliation(s)
- Fadi Bou‐Abdallah
- Department of ChemistryState University of New YorkPotsdamNew YorkUSA
| | - Jeremie Fish
- Department of Electrical & Computer EngineeringCoulter School of Engineering, Clarkson UniversityPotsdamNew YorkUSA
| | - Genki Terashi
- Department of Biological Sciences and Department of Computer SciencePurdue UniversityWest LafayetteIndianaUSA
| | - Yuanyuan Zhang
- Department of Biological Sciences and Department of Computer SciencePurdue UniversityWest LafayetteIndianaUSA
| | - Daisuke Kihara
- Department of Biological Sciences and Department of Computer SciencePurdue UniversityWest LafayetteIndianaUSA
| | - Paolo Arosio
- Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
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5
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Charif SE, Dorfman VB. Melatonin, modulation of hypothalamic activity, and reproduction. VITAMINS AND HORMONES 2024; 127:283-303. [PMID: 39864944 DOI: 10.1016/bs.vh.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Light is the most reliable environmental cue allowing animals to breed successfully when conditions are optimal. In seasonal breeders, photoperiod (length of daylight) information is sensed by the eyes and transmitted to the suprachiasmatic nucleus, the master clock region located in the hypothalamus. This structure has a 24-h firing rhythm involving a cycle of clock protein synthesis and degradation, and provides the timing to synchronize the synthesis and release of melatonin, the chemical signal that transduces the photoperiod information. The enzyme arylalkylamine N-acetyltransferase, responsible for melatonin synthesis in the pineal gland, is modulated by environmental light. Melatonin is secreted during the dark hours of the night to blood circulation and cerebrospinal fluid conveying photoperiod information to other tissues. Melatonin exerts its action by binding to specific membrane receptors MT1 and MT2, and can modulate several pathways including neurotransmitters, and hormones like kisspeptin, the gonadotropin-inhibitory hormone, and thyroid hormones, all of them impacting on gonadotropin-releasing hormone (GnRH) secretion. Then, GnRH will modulate in turn the reproductive axis. In conclusion, acting as a transducer of photoperiod information, this hormone exerts precisely timed activation of different pathways that modulate seasonal breeding ensuring optimal conditions for reproduction.
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Affiliation(s)
- Santiago Elías Charif
- Instituto de Tecnología (INTEC), Universidad Argentina de la Empresa (UADE), Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Verónica Berta Dorfman
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina.
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6
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Okamoto HH, Cecon E, Nureki O, Rivara S, Jockers R. Melatonin receptor structure and signaling. J Pineal Res 2024; 76:e12952. [PMID: 38587234 DOI: 10.1111/jpi.12952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/05/2024] [Accepted: 03/24/2024] [Indexed: 04/09/2024]
Abstract
Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.
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Affiliation(s)
- Hiroyuki H Okamoto
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Erika Cecon
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Silvia Rivara
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Ralf Jockers
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
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7
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Felder-Schmittbuhl MP, Hicks D, Ribelayga CP, Tosini G. Melatonin in the mammalian retina: Synthesis, mechanisms of action and neuroprotection. J Pineal Res 2024; 76:e12951. [PMID: 38572848 DOI: 10.1111/jpi.12951] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/09/2024] [Accepted: 03/19/2024] [Indexed: 04/05/2024]
Abstract
Melatonin is an important player in the regulation of many physiological functions within the body and in the retina. Melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Retinal melatonin is primarily synthesized by the photoreceptors, but whether the synthesis occurs in the rods and/or cones is still unclear. Melatonin exerts its influence by binding to G protein-coupled receptors named melatonin receptor type 1 (MT1) and type 2 (MT2). MT1 and MT2 receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they may form MT1/MT2 heteromers (MT1/2h). Studies in rodents have shown that melatonin signaling plays an important role in the regulation of retinal dopamine levels, rod/cone coupling as well as the photopic and scotopic electroretinogram. In addition, melatonin may play an important role in protecting photoreceptors from oxidative stress and can protect photoreceptors from apoptosis. Critically, melatonin signaling is involved in the modulation of photoreceptor viability during aging and other studies have implicated melatonin in the pathogenesis of age-related macular degeneration. Hence melatonin may represent a useful tool in the fight to protect photoreceptors-and other retinal cells-against degeneration due to aging or diseases.
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Affiliation(s)
- Marie Paule Felder-Schmittbuhl
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives (UPR 3212), Université de Strasbourg, Strasbourg, France
| | - David Hicks
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives (UPR 3212), Université de Strasbourg, Strasbourg, France
| | - Christophe P Ribelayga
- Department of Vision Sciences, College of Optometry, University of Houston, Houston, Texas, USA
| | - Gianluca Tosini
- Department of Pharmacology & Toxicology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA
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8
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Somalo-Barranco G, Pagano Zottola AC, Abdulrahman AO, El Zein RM, Cannich A, Muñoz L, Serra C, Oishi A, Marsicano G, Masri B, Bellocchio L, Llebaria A, Jockers R. Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration. Cell Chem Biol 2023; 30:920-932.e7. [PMID: 37572668 DOI: 10.1016/j.chembiol.2023.07.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 04/16/2023] [Accepted: 07/20/2023] [Indexed: 08/14/2023]
Abstract
The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1 receptors.
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Affiliation(s)
- Gloria Somalo-Barranco
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France; MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
| | | | | | - Rami M El Zein
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France
| | - Astrid Cannich
- INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France
| | - Lourdes Muñoz
- MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain; SIMChem, Synthesis of High Added Value Molecules, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
| | - Carme Serra
- MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain; SIMChem, Synthesis of High Added Value Molecules, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
| | - Atsuro Oishi
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France
| | - Giovanni Marsicano
- INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France
| | - Bernard Masri
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France
| | - Luigi Bellocchio
- INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France
| | - Amadeu Llebaria
- MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
| | - Ralf Jockers
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France.
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9
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Caniceiro AB, Bueschbell B, Schiedel AC, Moreira IS. Class A and C GPCR Dimers in Neurodegenerative Diseases. Curr Neuropharmacol 2022; 20:2081-2141. [PMID: 35339177 PMCID: PMC9886835 DOI: 10.2174/1570159x20666220327221830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 02/21/2022] [Accepted: 03/23/2022] [Indexed: 11/22/2022] Open
Abstract
Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases, the involvement of G proteincoupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and had already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence.
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Affiliation(s)
- Ana B. Caniceiro
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; ,These authors contributed equally to this work.
| | - Beatriz Bueschbell
- PhD Programme in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, 3030-789 Coimbra, Portugal; ,These authors contributed equally to this work.
| | - Anke C. Schiedel
- Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany;
| | - Irina S. Moreira
- University of Coimbra, Department of Life Sciences, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; ,Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal,Address correspondence to this author at the Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal; E-mail:
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10
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Somalo-Barranco G, Serra C, Lyons D, Piggins HD, Jockers R, Llebaria A. Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors. J Med Chem 2022; 65:11229-11240. [PMID: 35930058 PMCID: PMC9421648 DOI: 10.1021/acs.jmedchem.2c00717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
![]()
Melatonin is a neurohormone released in a circadian manner
with
peak levels at night. Melatonin mediates its effects mainly through
G protein-coupled MT1 and MT2 receptors. Drugs
acting on melatonin receptors are indicated for circadian rhythm-
and sleep-related disorders. Tools to study the activation of these
receptors with high temporal resolution are lacking. Here, we synthesized
a family of light-activatable caged compounds by attaching o-nitrobenzyl (o-NB) or coumarin photocleavable
groups to melatonin indolic nitrogen. All caged compounds showed the
expected decrease in binding affinity for MT1 and MT2. The o-NB derivative MCS-0382 showed the
best uncaging and biological properties, with 250-fold increase in
affinity and potency upon illumination. Generation of melatonin from
MCS-0382 was further demonstrated by its ability to modulate the excitation
of SCN neurons in rat brain slices. MCS-0382 is available to study
melatonin effects in a temporally controlled manner in cellular and
physiological settings.
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Affiliation(s)
- Gloria Somalo-Barranco
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France.,MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain
| | - Carme Serra
- MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.,SIMChem, Synthesis of High Added Value Molecules, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain
| | - David Lyons
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, BS8 1TD Bristol, U.K
| | - Hugh D Piggins
- School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, BS8 1TD Bristol, U.K
| | - Ralf Jockers
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France
| | - Amadeu Llebaria
- MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain
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11
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Gbahou F, Levin S, Tikhonova IG, Somalo Barranco G, Izabelle C, Ohana RF, Jockers R. Luminogenic HiBiT Peptide-Based NanoBRET Ligand Binding Assays for Melatonin Receptors. ACS Pharmacol Transl Sci 2022; 5:668-678. [DOI: 10.1021/acsptsci.2c00096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Florence Gbahou
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France
| | - Sergiy Levin
- Promega Corporation, Fitchburg, Wisconsin 53711, United States
| | - Irina G. Tikhonova
- School of Pharmacy, Medical Biology Centre, Queen’s University Belfast, Belfast BT9 7BL, United Kingdom
| | | | - Charlotte Izabelle
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France
| | | | - Ralf Jockers
- Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France
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12
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Melatonin Receptors: A Key Mediator in Animal Reproduction. Vet Sci 2022; 9:vetsci9070309. [PMID: 35878326 PMCID: PMC9320721 DOI: 10.3390/vetsci9070309] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/16/2022] [Accepted: 06/20/2022] [Indexed: 01/26/2023] Open
Abstract
Melatonin, a hormone produced by the mammalian pineal gland, influences various physiological activities, many of which are related to animal reproduction, including neuroendocrine function, rhythm regulation, seasonal behavior, gonadogenesis, gamete development and maturation, sexual maturation, and thermoregulation. Melatonin exerts beneficial actions mainly via binding with G-protein-coupled receptors (GPCR), termed MT1 and MT2. Melatonin receptors are crucial for mediating animal reproduction. This paper reviews the characteristics of melatonin receptors including MT1 and MT2, as well as their roles in mediating signal transduction and biological effects, with a focus on their function in animal reproduction. In addition, we briefly summarize the developments in pharmacological research regarding melatonin receptors as drug targets. It is expected that this review will provide a reference for further exploration and unveiling of melatonin receptor function in reproductive regulation.
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Fernández-Alegre E, Lacalle E, Soriano-Úbeda C, González-Montaña JR, Domínguez JC, Casao A, Martínez-Pastor F. Bos taurus and Cervus elaphus as Non-Seasonal/Seasonal Models for the Role of Melatonin Receptors in the Spermatozoon. Int J Mol Sci 2022; 23:ijms23116284. [PMID: 35682961 PMCID: PMC9181011 DOI: 10.3390/ijms23116284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/28/2022] [Accepted: 06/01/2022] [Indexed: 02/04/2023] Open
Abstract
Melatonin is crucial in reproduction due its antioxidant, hormonal, and paracrine action. Melatonin membrane receptors (MT1/MT2) have been confirmed on spermatozoa from several species, but functionality studies are scarce. To clarify their role in ruminants as reproductive models, bull (Bos taurus, non-seasonal) and red deer (Cervus elaphus, highly seasonal) spermatozoa were analyzed after 4 h of incubation (38 °C, capacitating media) in 10 nM melatonin, MT1/MT2 agonists (phenylmelatonin and 8M-PDOT), and antagonists (luzindole and 4P-PDOT). Motility and functionality (flow cytometry: viability, intracellular calcium, capacitation status, reactive oxygen species (ROS) production, and acrosomal and mitochondrial status) were assessed. In bull, MT1 was related to sperm viability preservation, whereas MT2 could modulate cell functionality to prevent excess ROS produced by the mitochondria; this action could have a role in modulating sperm capacitation. Deer spermatozoa showed resistance to melatonin and receptor activation, possibly because the samples were of epididymal origin and collected at the breeding season's peak, with high circulating melatonin. However, receptors could be involved in mitochondrial protection. Therefore, melatonin receptors are functional in the spermatozoa from bull and deer, with different activities. These species offer models differing from traditional laboratory experimental animals on the role of melatonin in sperm biology.
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Affiliation(s)
- Estela Fernández-Alegre
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Bianor Biotech SL, 24071 Leon, Spain
| | - Estíbaliz Lacalle
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Bianor Biotech SL, 24071 Leon, Spain
| | - Cristina Soriano-Úbeda
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Department of Molecular Biology (Cell Biology), University of León, 24071 Leon, Spain
| | - José Ramiro González-Montaña
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Department of Medicine, Surgery and Veterinary Anatomy (Animal Medicine and Surgery), University of León, 24071 Leon, Spain
| | - Juan Carlos Domínguez
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Department of Medicine, Surgery and Veterinary Anatomy (Animal Medicine and Surgery), University of León, 24071 Leon, Spain
| | - Adriana Casao
- Department of Biochemistry and Molecular and Cell Biology, Institute of Environmental Sciences of Aragón, School of Veterinary Medicine, University of Zaragoza, 50013 Zaragoza, Spain;
| | - Felipe Martínez-Pastor
- Institute of Animal Health and Cattle Development (INDEGSAL), University of León, 24071 Leon, Spain; (E.F.-A.); (E.L.); (C.S.-Ú.); (J.R.G.-M.); (J.C.D.)
- Department of Molecular Biology (Cell Biology), University of León, 24071 Leon, Spain
- Correspondence: ; Tel.: +34-987-291-491
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14
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Zhao Y, Shao G, Liu X, Li Z. Assessment of the Therapeutic Potential of Melatonin for the Treatment of Osteoporosis Through a Narrative Review of Its Signaling and Preclinical and Clinical Studies. Front Pharmacol 2022; 13:866625. [PMID: 35645810 PMCID: PMC9130700 DOI: 10.3389/fphar.2022.866625] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/06/2022] [Indexed: 12/21/2022] Open
Abstract
Melatonin is a bioamine produced primarily in the pineal gland, although peripheral sites, including the gut, may also be its minor source. Melatonin regulates various functions, including circadian rhythm, reproduction, temperature regulation, immune system, cardiovascular system, energy metabolism, and bone metabolism. Studies on cultured bone cells, preclinical disease models of bone loss, and clinical trials suggest favorable modulation of bone metabolism by melatonin. This narrative review gives a comprehensive account of the current understanding of melatonin at the cell/molecular to the systems levels. Melatonin predominantly acts through its cognate receptors, of which melatonin receptor 2 (MT2R) is expressed in mesenchymal stem cells (MSCs), osteoblasts (bone-forming), and osteoclasts (bone-resorbing). Melatonin favors the osteoblastic fate of MSCs, stimulates osteoblast survival and differentiation, and inhibits osteoclastogenic differentiation of hematopoietic stem cells. Produced from osteoblastic cells, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) critically regulate osteoclastogenesis and melatonin by suppressing the osteoclastogenic RANKL, and upregulating the anti-osteoclastogenic OPG exerts a strong anti-resorptive effect. Although the anti-inflammatory role of melatonin favors osteogenic function and antagonizes the osteoclastogenic function with the participation of SIRT signaling, various miRNAs also mediate the effects of the hormone on bone cells. In rodent models of osteoporosis, melatonin has been unequivocally shown to have an anti-osteoporotic effect. Several clinical trials indicate the bone mass conserving effect of melatonin in aging/postmenopausal osteoporosis. This review aims to determine the possibility of melatonin as a novel class of anti-osteoporosis therapy through the critical assessment of the available literature.
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Affiliation(s)
- Yongchao Zhao
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Guoxi Shao
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Xingang Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Zhengwei Li
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
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15
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Biringer RG. Migraine signaling pathways: amino acid metabolites that regulate migraine and predispose migraineurs to headache. Mol Cell Biochem 2022; 477:2269-2296. [PMID: 35482233 DOI: 10.1007/s11010-022-04438-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
Abstract
Migraine is a common, debilitating disorder for which attacks typically result in a throbbing, pulsating headache. Although much is known about migraine, its complexity renders understanding the complete etiology currently out of reach. However, two important facts are clear, the brain and the metabolism of the migraineur differ from that of the non-migraineur. This review centers on the altered amino acid metabolism in migraineurs and how it helps define the pathology of migraine.
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Affiliation(s)
- Roger Gregory Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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16
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Wu N, Carpino G, Ceci L, Baiocchi L, Francis H, Kennedy L, Zhou T, Chen L, Sato K, Kyritsi K, Meadows V, Ekser B, Franchitto A, Mancinelli R, Onori P, Gaudio E, Glaser S, Alpini G. Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury. Hepatology 2022; 75:797-813. [PMID: 34743371 PMCID: PMC8930565 DOI: 10.1002/hep.32233] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 10/29/2021] [Accepted: 11/05/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIMS Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form heterodimers and homodimers, but MT1 and MT2 can heterodimerize with the orphan receptor G protein-coupled receptor 50 (GPR50). MT1/GPR50 dimerization blocks melatonin binding, but MT2/GPR50 dimerization does not affect melatonin binding. GPR50 can dimerize with TGFβ receptor type I (TGFβRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis. APPROACH AND RESULTS Wild-type (WT), MT1 knockout (KO), MT2KO, and MT1/MT2 double KO (DKO) mice underwent sham or bile duct ligation (BDL); these mice were also treated with melatonin. BDL WT and multidrug resistance 2 KO (Mdr2-/- ) mice received mismatch, MT1, or MT2 Vivo-Morpholino. Biliary expression of MT1 and GPR50 increases in cholestatic rodents and human primary sclerosing cholangitis (PSC) samples. Loss of MT1 in BDL and Mdr2-/- mice ameliorated biliary and liver damage, whereas these parameters were enhanced following loss of MT2 and in DKO mice. Interestingly, melatonin treatment alleviated BDL-induced biliary and liver injury in BDL WT and BDL MT2KO mice but not in BDL MT1KO or BDL DKO mice, demonstrating melatonin's interaction with MT1. Loss of MT2 or DKO mice exhibited enhanced GPR50/TGFβR1 signaling, which was reduced by loss of MT1. CONCLUSIONS Melatonin ameliorates liver phenotypes through MT1, whereas down-regulation of MT2 promotes liver damage through GPR50/TGFβR1 activation. Blocking GPR50/TGFβR1 binding through modulation of melatonin signaling may be a therapeutic approach for PSC.
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Affiliation(s)
- Nan Wu
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, Rome, Italy
| | - Ludovica Ceci
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | | | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Tianhao Zhou
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Lixian Chen
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Konstantina Kyritsi
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Vik Meadows
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
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17
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Ferré S, Ciruela F, Dessauer CW, González-Maeso J, Hébert TE, Jockers R, Logothetis DE, Pardo L. G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs). Pharmacol Ther 2022; 231:107977. [PMID: 34480967 PMCID: PMC9375844 DOI: 10.1016/j.pharmthera.2021.107977] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/11/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022]
Abstract
G protein-coupled receptors (GPCRs) are the largest group of receptors involved in cellular signaling across the plasma membrane and a major class of drug targets. The canonical model for GPCR signaling involves three components - the GPCR, a heterotrimeric G protein and a proximal plasma membrane effector - that have been generally thought to be freely mobile molecules able to interact by 'collision coupling'. Here, we synthesize evidence that supports the existence of GPCR-effector macromolecular membrane assemblies (GEMMAs) comprised of specific GPCRs, G proteins, plasma membrane effector molecules and other associated transmembrane proteins that are pre-assembled prior to receptor activation by agonists, which then leads to subsequent rearrangement of the GEMMA components. The GEMMA concept offers an alternative and complementary model to the canonical collision-coupling model, allowing more efficient interactions between specific signaling components, as well as the integration of the concept of GPCR oligomerization as well as GPCR interactions with orphan receptors, truncated GPCRs and other membrane-localized GPCR-associated proteins. Collision-coupling and pre-assembled mechanisms are not exclusive and likely both operate in the cell, providing a spectrum of signaling modalities which explains the differential properties of a multitude of GPCRs in their different cellular environments. Here, we explore the unique pharmacological characteristics of individual GEMMAs, which could provide new opportunities to therapeutically modulate GPCR signaling.
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Affiliation(s)
- Sergi Ferré
- Integrative Neurobiology Section, National Institute on Drug Addiction, Intramural Research Program, NIH, DHHS, Baltimore, MD, USA.
| | - Francisco Ciruela
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Spain
| | - Carmen W. Dessauer
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Terence E. Hébert
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec
| | - Ralf Jockers
- University of Paris, Institute Cochin, INSERM, CNRS, Paris, France
| | - Diomedes E. Logothetis
- Laboratory of Electrophysiology, Departments of Pharmaceutical Sciences, Chemistry and Chemical Biology and Center for Drug Discovery, School of Pharmacy at the Bouvé College of Health Sciences and College of Science, Northeastern University, Boston, Massachusetts, USA
| | - Leonardo Pardo
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain
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18
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Oishi A, Jockers R. Measuring Protein-Protein Interactions of Melatonin Receptors by Bioluminescence Resonance Energy Transfer (BRET). Methods Mol Biol 2022; 2550:207-218. [PMID: 36180695 DOI: 10.1007/978-1-0716-2593-4_26] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The melatonin receptor subfamily belongs to the G protein-coupled receptor superfamily and consists of three members in mammals, MT1, MT2, and GPR50. These receptors can interact with each other to form homo- and heterodimers that are part of larger molecular complexes composed of G proteins, β-arrestins, and other membrane and cytosolic proteins. BRET (bioluminescence resonance energy transfer) is a versatile technique to follow protein-protein interactions on the nanometer scale, in real time, in living cells, which contributed largely to our understanding of the function of melatonin receptors. In this chapter, we describe our BRET protocols for melatonin receptors, which can also be applied to other GPCRs.
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Affiliation(s)
- Atsuro Oishi
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
- Department of Anatomy, Kyorin University Faculty of Medicine, Tokyo, Japan
- Cancer RNA Research Unit, National Cancer Center Research Institute, Tokyo, Japan
| | - Ralf Jockers
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.
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19
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Nikolaev G, Robeva R, Konakchieva R. Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease. Int J Mol Sci 2021; 23:ijms23010471. [PMID: 35008896 PMCID: PMC8745360 DOI: 10.3390/ijms23010471] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology-for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.
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Affiliation(s)
- Georgi Nikolaev
- Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1504 Sofia, Bulgaria;
- Correspondence:
| | - Ralitsa Robeva
- Department of Endocrinology, Faculty of Medicine, Medical University, 1431 Sofia, Bulgaria;
| | - Rossitza Konakchieva
- Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1504 Sofia, Bulgaria;
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20
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Parmar S, Tadavarty R, Sastry BR. G-protein coupled receptors and synaptic plasticity in sleep deprivation. World J Psychiatry 2021; 11:954-980. [PMID: 34888167 PMCID: PMC8613756 DOI: 10.5498/wjp.v11.i11.954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/05/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Insufficient sleep has been correlated to many physiological and psychoneurological disorders. Over the years, our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes. In addition, during sleep, electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system (CNS). Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour. Memory consolidation and learning that take place during sleep cycles, can be affected by changes in synaptic plasticity during sleep disturbances. G-protein coupled receptors (GPCRs), with their versatile structural and functional attributes, can regulate synaptic plasticity in CNS and hence, may be potentially affected in sleep deprived conditions. In this review, we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
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Affiliation(s)
- Shweta Parmar
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Ramakrishna Tadavarty
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Bhagavatula R Sastry
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
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21
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Shabajee-Alibay P, Bonnaud A, Malpaux B, Delagrange P, Audinot V, Yous S, Boutin JA, Stephan JP, Leprince J, Legros C. A putative new melatonin binding site in sheep brain, MTx: preliminary observations and characteristics. J Pharmacol Exp Ther 2021; 380:JPET-AR-2021-000785. [PMID: 34706966 DOI: 10.1124/jpet.121.000785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/29/2021] [Accepted: 10/22/2021] [Indexed: 11/22/2022] Open
Abstract
In mammals, MT1 and MT2 melatonin receptors are high affinity G protein-coupled receptors and are thought to be involved in the integration of the melatonin signaling throughout the brain and periphery. In the present study, we describe a new melatonin binding site, named MTx, with a peculiar pharmacological profile. This site had a low affinity for 2-[125I]-melatonin in saturation assays in hypothalamus and retina (pKD = 9.13 {plus minus} 0.05, Bmax = 1.12 {plus minus} 0.11 fmol/mg protein and pKD = 8.81 {plus minus} 0.50, Bmax = 7.65 {plus minus} 2.64 fmol/mg protein, respectively) and a very high affinity, in competition assays, for melatonin (pKi = 13.08 {plus minus} 0.18), and other endogenous compounds. Using autoradiography, we showed a preferential localization of the MTx in periventricular areas of the sheep brain, with a density 3 to 8 times higher than those observed for ovine MT1 In addition, using a set of well-characterized ligands, we showed that this site did not correspond to any of the following receptors: MT1, MT2, MT3 , D1, D2, noradrenergic, nor 5-HT2 Based on its affinity for melatonin, MTx did not seem to be implicated in the integration of cerebral melatonin concentration variations since they were saturating for MTx. Nevertheless, it remained of prime importance because of its periventricular distribution, in close contact with the CSF, and its peculiar pharmacological profile responding to both melatoninergic and serotoninergic compounds. Significance Statement Herein a putative new melatonin binding site is described in sheep brain parts in close contact with the 3rd ventricle. The characteristics of the pharmacological profile of this site is different from anything previously reported in the literature. The present work forms the basis of future full pharmacological characterization.
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Affiliation(s)
- Preety Shabajee-Alibay
- Laboratoire de Différenciation et Communication Neuronale et Neuroendocrine, Normandie Université, UNIROUEN, INSERM 1239, France
| | | | - Benoit Malpaux
- UMR Physiologie de la Reproduction et des Comportements, INRA Val de Loire, France
| | | | | | - Said Yous
- UMR-S 1172-LiNC-Lille Neuroscience & Cognition, Univ. Lille, INSERM, CHU Lille, France
| | - Jean A Boutin
- Institut de Recherches Internationales Servier, France
| | | | - Jérôme Leprince
- Laboratoire de Différenciation et Communication Neuronale et Neuroendocrine, Normandie Université, UNIROUEN, INSERM 1239, France
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22
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Tse LH, Wong YH. Modeling the Heterodimer Interfaces of Melatonin Receptors. Front Cell Neurosci 2021; 15:725296. [PMID: 34690701 PMCID: PMC8529217 DOI: 10.3389/fncel.2021.725296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022] Open
Abstract
Melatonin receptors are Class A G protein-coupled receptors (GPCRs) that regulate a plethora of physiological activities in response to the rhythmic secretion of melatonin from the pineal gland. Melatonin is a key regulator in the control of circadian rhythm and has multiple functional roles in retinal physiology, memory, immunomodulation and tumorigenesis. The two subtypes of human melatonin receptors, termed MT1 and MT2, utilize overlapping signaling pathways although biased signaling properties have been reported in some cellular systems. With the emerging concept of GPCR dimerization, melatonin receptor heterodimers have been proposed to participate in system-biased signaling. Here, we used computational approaches to map the dimerization interfaces of known heterodimers of melatonin receptors, including MT1/MT2, MT1/GPR50, MT2/GPR50, and MT2/5-HT2C. By homology modeling and membrane protein docking analyses, we have identified putative preferred interface interactions within the different pairs of melatonin receptor dimers and provided plausible structural explanations for some of the unique pharmacological features of specific heterodimers previously reported. A thorough understanding of the molecular basis of melatonin receptor heterodimers may enable the development of new therapeutic approaches against aliments involving these heterodimeric receptors.
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Affiliation(s)
- Lap Hang Tse
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, SAR China
| | - Yung Hou Wong
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, SAR China.,State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, SAR China.,Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, SAR China
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23
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Zhou Y, Meng J, Xu C, Liu J. Multiple GPCR Functional Assays Based on Resonance Energy Transfer Sensors. Front Cell Dev Biol 2021; 9:611443. [PMID: 34041234 PMCID: PMC8141573 DOI: 10.3389/fcell.2021.611443] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022] Open
Abstract
G protein-coupled receptors (GPCRs) represent one of the largest membrane protein families that participate in various physiological and pathological activities. Accumulating structural evidences have revealed how GPCR activation induces conformational changes to accommodate the downstream G protein or β-arrestin. Multiple GPCR functional assays have been developed based on Förster resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) sensors to monitor the conformational changes in GPCRs, GPCR/G proteins, or GPCR/β-arrestin, especially over the past two decades. Here, we will summarize how these sensors have been optimized to increase the sensitivity and compatibility for application in different GPCR classes using various labeling strategies, meanwhile provide multiple solutions in functional assays for high-throughput drug screening.
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Affiliation(s)
- Yiwei Zhou
- Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Jiyong Meng
- Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Chanjuan Xu
- Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Jianfeng Liu
- Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
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Rui T, Wang H, Li Q, Cheng Y, Gao Y, Fang X, Ma X, Chen G, Gao C, Gu Z, Song S, Zhang J, Wang C, Wang Z, Wang T, Zhang M, Min J, Chen X, Tao L, Wang F, Luo C. Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis. J Pineal Res 2021; 70:e12704. [PMID: 33206394 DOI: 10.1111/jpi.12704] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 12/16/2022]
Abstract
Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.
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Affiliation(s)
- Tongyu Rui
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Haochen Wang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Qianqian Li
- School of Forensic Medicine, Wannan Medical College, Wuhu, China
| | - Ying Cheng
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Yuan Gao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Xuexian Fang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuying Ma
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Guang Chen
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Cheng Gao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Zhiya Gu
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Shunchen Song
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Jian Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunling Wang
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zufeng Wang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Tao Wang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Mingyang Zhang
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Junxia Min
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiping Chen
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Luyang Tao
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
| | - Fudi Wang
- The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengliang Luo
- Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China
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Influence of Circadian Rhythm in the Eye: Significance of Melatonin in Glaucoma. Biomolecules 2021; 11:biom11030340. [PMID: 33668357 PMCID: PMC7996162 DOI: 10.3390/biom11030340] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Circadian rhythm and the molecules involved in it, such as melanopsin and melatonin, play an important role in the eye to regulate the homeostasis and even to treat some ocular conditions. As a result, many ocular pathologies like dry eye, corneal wound healing, cataracts, myopia, retinal diseases, and glaucoma are affected by this cycle. This review will summarize the current scientific literature about the influence of circadian patterns on the eye, focusing on its relationship with increased intraocular pressure (IOP) fluctuations and glaucoma. Regarding treatments, two ways should be studied: the first one, to analyze if some treatments could improve their effect on the ocular disease when their posology is established in function of circadian patterns, and the second one, to evaluate new drugs to treat eye pathologies related to the circadian rhythm, as it has been stated with melatonin or its analogs, that not only could be used as the main treatment but as coadjutant, improving the circadian pattern or its antioxidant and antiangiogenic properties.
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Liu PI, Chang AC, Lai JL, Lin TH, Tsai CH, Chen PC, Jiang YJ, Lin LW, Huang WC, Yang SF, Tang CH. Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases. Oncogene 2021; 40:1503-1515. [PMID: 33452455 DOI: 10.1038/s41388-020-01613-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 12/06/2020] [Accepted: 12/10/2020] [Indexed: 01/29/2023]
Abstract
Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.
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Affiliation(s)
- Po-I Liu
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,Department of General Thoracic Surgery, Asia University Hospital, Taichung, Taiwan
| | - An-Chen Chang
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Jiun-Lin Lai
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Tien-Huang Lin
- Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.,School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chun-Hao Tsai
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Po-Chun Chen
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Ya-Jing Jiang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Liang-Wei Lin
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chien Huang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. .,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan. .,School of Medicine, China Medical University, Taichung, Taiwan. .,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan. .,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
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27
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Johnstone EKM, See HB, Abhayawardana RS, Song A, Rosengren KJ, Hill SJ, Pfleger KDG. Investigation of Receptor Heteromers Using NanoBRET Ligand Binding. Int J Mol Sci 2021; 22:1082. [PMID: 33499147 PMCID: PMC7866079 DOI: 10.3390/ijms22031082] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/20/2022] Open
Abstract
Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its constituent receptor units. Detection of these complexes and monitoring their pharmacology is crucial for understanding how receptors function. The Receptor-Heteromer Investigation Technology (Receptor-HIT) utilizes ligand-dependent modulation of interactions between receptors and specific biomolecules for the detection and profiling of heteromer complexes. Previously, the interacting biomolecules used in Receptor-HIT assays have been intracellular proteins, however in this study we have for the first time used bioluminescence resonance energy transfer (BRET) with fluorescently-labeled ligands to investigate heteromerization of receptors on the cell surface. Using the Receptor-HIT ligand binding assay with NanoBRET, we have successfully investigated heteromers between the angiotensin II type 1 (AT1) receptor and the β2 adrenergic receptor (AT1-β2AR heteromer), as well as between the AT1 and angiotensin II type 2 receptor (AT1-AT2 heteromer).
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Affiliation(s)
- Elizabeth K. M. Johnstone
- Molecular Endocrinology and Pharmacology Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; (H.B.S.); (R.S.A.); (S.J.H.)
- Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Canberra, NSW 2609, Australia
| | - Heng B. See
- Molecular Endocrinology and Pharmacology Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; (H.B.S.); (R.S.A.); (S.J.H.)
- Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Canberra, NSW 2609, Australia
| | - Rekhati S. Abhayawardana
- Molecular Endocrinology and Pharmacology Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; (H.B.S.); (R.S.A.); (S.J.H.)
- Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Canberra, NSW 2609, Australia
| | - Angela Song
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia; (A.S.); (K.J.R.)
| | - K. Johan Rosengren
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia; (A.S.); (K.J.R.)
| | - Stephen J. Hill
- Molecular Endocrinology and Pharmacology Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; (H.B.S.); (R.S.A.); (S.J.H.)
- Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
- Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
- Centre of Membrane Proteins and Receptors, University of Nottingham, Midlands NG7 2UH, UK
| | - Kevin D. G. Pfleger
- Molecular Endocrinology and Pharmacology Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; (H.B.S.); (R.S.A.); (S.J.H.)
- Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Canberra, NSW 2609, Australia
- Dimerix Limited, Nedlands, WA 6009, Australia
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28
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Gerbier R, Ndiaye-Lobry D, Martinez de Morentin PB, Cecon E, Heisler LK, Delagrange P, Gbahou F, Jockers R. Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5-HT 2C receptor heteromers in mouse brain. FASEB J 2020; 35:e21161. [PMID: 33156577 DOI: 10.1096/fj.202000305r] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 10/08/2020] [Accepted: 10/19/2020] [Indexed: 01/01/2023]
Abstract
Association of G protein-coupled receptors into heterodimeric complexes has been reported for over 50 receptor pairs in vitro but functional in vivo validation remains a challenge. Our recent in vitro studies defined the functional fingerprint of heteromers composed of Gi -coupled melatonin MT2 receptors and Gq -coupled serotonin 5-HT2C receptors, in which melatonin transactivates phospholipase C (PLC) through 5-HT2C . Here, we identified this functional fingerprint in the mouse brain. Gq protein activation was probed by [35 S]GTPγS incorporation followed by Gq immunoprecipitation, and PLC activation by determining the inositol phosphate levels in brain lysates of animals previously treated with melatonin. Melatonin concentration-dependently activated Gq proteins and PLC in the hypothalamus and cerebellum but not in cortex. These effects were inhibited by the 5-HT2C receptor-specific inverse agonist SB-243213, and were absent in MT2 and 5-HT2C knockout mice, fully recapitulating previous in vitro data and indicating the involvement of MT2 /5-HT2C heteromers. The antidepressant agomelatine had a similar effect than melatonin when applied alone but blocked the melatonin-promoted Gq activation due to its 5-HT2C antagonistic component. Collectively, we provide strong functional evidence for the existence of MT2 /5-HT2C heteromeric complexes in mouse brain. These heteromers might participate in the in vivo effects of agomelatine.
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Affiliation(s)
- Romain Gerbier
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | | | | | - Erika Cecon
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | | | | | - Florence Gbahou
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Ralf Jockers
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
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Scuderi L, Davinelli S, Iodice CM, Bartollino S, Scapagnini G, Costagliola C, Scuderi G. Melatonin: Implications for Ocular Disease and Therapeutic Potential. Curr Pharm Des 2020; 25:4185-4191. [PMID: 31724508 DOI: 10.2174/1381612825666191113110225] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 11/12/2019] [Indexed: 02/08/2023]
Abstract
Melatonin, an indoleamine secreted mainly by the pineal gland, is known to modulate a wide range of circadian functions. However, this neurohormone is also synthesized within the eye and acts directly on ocular structures to mediate a variety of physiological processes. This review is focused on the role and therapeutic potential of melatonin in ocular diseases. We summarize data indicating that melatonin may represent a powerful tool to counteract ocular dysfunctions such as uveitis, glaucoma, age-related macular degeneration, and diabetic retinopathy. A search strategy was conducted to identify studies in PubMed (January 1990 to September 2017). In particular, we included experimental studies, clinical trials, and reviews to provide suitable insights and elucidations regarding the action of melatonin on age-related ocular disorders. Literature data suggest that melatonin could potentially protect ocular tissues by decreasing the production of free radicals and pro-inflammatory mediators. Additionally, melatonin appears to be safe and well-tolerated, even at high doses, and no adverse/side effects were reported. Although this topic remains under intense investigation, we can conclude that melatonin, as a single agent or in combination with other drugs, is an attractive pharmacological candidate for age-related ocular diseases.
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Affiliation(s)
- Luca Scuderi
- Neuroscience, Mental Health and Sense Organs Department, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Rome, Italy
| | - Sergio Davinelli
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Clemente Maria Iodice
- Neuroscience, Mental Health and Sense Organs Department, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Rome, Italy
| | - Silvia Bartollino
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giovanni Scapagnini
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Ciro Costagliola
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Gianluca Scuderi
- Neuroscience, Mental Health and Sense Organs Department, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Rome, Italy
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30
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Melatonin membrane receptors MT 1 and MT 2 are expressed in ram spermatozoa from non-seasonal breeds. Trop Anim Health Prod 2020; 52:2549-2557. [PMID: 32445158 DOI: 10.1007/s11250-020-02289-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 05/13/2020] [Indexed: 12/23/2022]
Abstract
In mammals, many melatonin biological functions are mediated through its interaction with the membrane receptors MT1 and MT2. We have previously reported their presence in ram spermatozoa from males located in temperate climates, but there is no information on their presence in spermatozoa from rams in areas with an equatorial photoperiod (12L:12D). Thus, we have investigated the existence and cellular distribution of melatonin receptors in spermatozoa from three sheep breeds in Colombia (Colombian Creole, Hampshire, and Romney Marsh) during dry and rainy seasons, using indirect immunofluorescence and western blot. Our results indicated the presence of melatonin receptors in spermatozoa from these rams, and that their distribution differs from that previously found in spermatozoa from rams in temperate climates. Moreover, two new immunotypes of MT2 were identified: type N, with staining only in the neck, and type E with a band of immunofluorescence in the upper part of the post-acrosome and the apical edge. Likewise, differences between breeds and climate seasons were detected for both receptors. However, densitometry analysis of western blot bands only revealed differences between seasons in the Creole rams for MT1 and the Romney Marsh rams for MT2, whereas differences between breeds were only detected for MT2. It could be inferred that melatonin receptors in rams subjected to an equatorial photoperiod might be more closely related to sperm quality than seasonal control. Therefore, the presence of these receptors suggests that melatonin could be a useful tool to increase the fertility of rams located in tropical or equatorial climates.
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31
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Lee BH, Bussi IL, de la Iglesia HO, Hague C, Koh DS, Hille B. Two indoleamines are secreted from rat pineal gland at night and act on melatonin receptors but are not night hormones. J Pineal Res 2020; 68:e12622. [PMID: 31715643 PMCID: PMC7007382 DOI: 10.1111/jpi.12622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 11/28/2022]
Abstract
INTRODUCTION At night, the pineal gland produces the indoleamines, melatonin, N-acetylserotonin (NAS), and N-acetyltryptamine (NAT). Melatonin is accepted as a hormone of night. Could NAS and NAT serve that role too? METHODS Concentration-response measurements with overexpressed human melatonin receptors MT1 and MT2 ; mass spectrometry analysis of norepinephrine-stimulated secretions from isolated rat pineal glands; analysis of 24-hour periodic samples of rat blood. RESULTS We show that NAT and NAS do activate melatonin receptors MT1 and MT2 , although with lower potency than melatonin, and that in vitro, melatonin and NAS are secreted from stimulated, isolated pineal glands in roughly equimolar amounts, but secretion of NAT was much less. All three were found at roughly equal concentrations in blood during the night. However, during the day, serum melatonin fell to very low values creating a high-amplitude circadian rhythm that was absent after pinealectomy, whereas NAS and NAT showed only small or no circadian variation. CONCLUSION Blood levels of NAS and NAT were insufficient to activate peripheral melatonin receptors, and they were invariant, so they could not serve as circulating hormones of night. However, they could instead act in paracrine circadian fashion near the pineal gland or via other higher-affinity receptors.
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Affiliation(s)
- Bo Hyun Lee
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
| | - Ivana L. Bussi
- Department of Biology, University of Washington School, Seattle, WA 98195-1800 USA
| | | | - Chris Hague
- Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
| | - Duk-Su Koh
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
- Co-corresponding authors: Bertil Hille; , Phone: 206-543-6661, Duk-Su Koh; , Phone: 206-407-6690
| | - Bertil Hille
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290 USA
- Co-corresponding authors: Bertil Hille; , Phone: 206-543-6661, Duk-Su Koh; , Phone: 206-407-6690
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32
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Alkozi HA, Navarro G, Aguinaga D, Reyes-Resina I, Sanchez-Naves J, Pérez de Lara MJ, Franco R, Pintor J. Adreno-melatonin receptor complexes control ion homeostasis and intraocular pressure - their disruption contributes to hypertensive glaucoma. Br J Pharmacol 2020; 177:2090-2105. [PMID: 31901203 DOI: 10.1111/bph.14971] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE Often, glaucoma presents with elevated eye hydrostatic pressure, which is regulated by endogenous melatonin. Phenylephrine increases cytoplasmic [Ca2+ ], via α1 -adrenoceptor activation, that is detrimental in glaucoma. The aims of this study were (a) to elucidate the role of melatonin receptors in humour production and intraocular pressure (IOP) maintenance and (b) to identify glaucoma-relevant melatonin-adrenoceptor interactions. EXPERIMENTAL APPROACH Biophysical and proximity ligation assays were performed to identify interactions in heterologous expression systems, in cell lines and in human eyes. Gs /Gi /Gq signalling was investigated in these systems and in cells producing aqueous humour. IOP was determined in a mice model of glaucoma. Retinography and topically pharmacological treatment were performed in control and in glaucomatous mice. KEY RESULTS α1 -adreno- and melatonin receptors form functional complexes in which the C-terminal tail of the adrenoceptor plays a role. Remarkably, activation of α1 -adrenoceptors in these complexes did not lead to cytosolic Ca2+ increases, suggesting Gs instead of Gq coupling is involved. The number of these complexes significantly decreased in models of glaucoma and, importantly, in human samples from glaucoma patients. This has led to hypothesize that melatonin, a hypotensive agent, plus blockade of α1 -adrenoceptors could normalize pressure in glaucoma. Remarkably, co-instillation of melatonin and prazosin, an α1 -adrenoceptor antagonist, resulted in long-term decreases in IOP in a well-established animal model of glaucoma. CONCLUSIONS AND IMPLICATIONS The findings are instrumental to understand the physiological function of melatonin in the eye and its potential to address eye pathologies by targeting melatonin receptors and their complexes.
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Affiliation(s)
- Hanan Awad Alkozi
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain
| | - Gemma Navarro
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.,Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain
| | - David Aguinaga
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.,Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Irene Reyes-Resina
- Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain.,Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Juan Sanchez-Naves
- Department of Ophthalmology, Balearic Islands Institute of Ophthalmology, Palma de Mallorca, Spain
| | - Maria J Pérez de Lara
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain
| | - Rafael Franco
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.,Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Jesus Pintor
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain
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Boutin JA, Legros C. The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion. Pharmacol Res Perspect 2020; 8:e00556. [PMID: 31893125 PMCID: PMC6935684 DOI: 10.1002/prp2.556] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/03/2019] [Accepted: 12/03/2019] [Indexed: 12/22/2022] Open
Abstract
Receptology has been complicated with enhancements in our knowledge of G-protein-coupled-receptor (GPCR) biochemistry. This complexity is exemplified by the pharmacology of melatonin receptors. Here, we describe the complexity of GPCR biochemistry in five dimensions: (a) receptor expression, particularly in organs/tissues that are only partially understood; (b) ligands and receptor-associated proteins (interactome); (c) receptor function, which might be more complex than the known G-protein-coupled systems; (d) ligand bias, which favors a particular pathway; and (e) receptor dimerization, which might concern all receptors coexpressed in the same cell. Thus, receptor signaling might be modified or modulated, depending on the nature of the receptor complex. Fundamental studies are needed to clarify these points and find new ways to tackle receptor functionality. This opinion article emphasizes the global questions attached to new descriptions of GPCRs and aims to raise our awareness of the tremendous complexity of modern receptology.
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Affiliation(s)
- Jean A. Boutin
- Institut de Recherches Internationales ServierSuresnesFrance
| | - Céline Legros
- Institut de Recherches ServierCroissy‐sur‐SeineFrance
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34
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Alkozi HA, Navarro G, Franco R, Pintor J. Melatonin and the control of intraocular pressure. Prog Retin Eye Res 2019; 75:100798. [PMID: 31560946 DOI: 10.1016/j.preteyeres.2019.100798] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/13/2019] [Accepted: 09/18/2019] [Indexed: 12/15/2022]
Abstract
Melatonin is not only synthesized by the pineal gland but by several ocular structures. This natural indoleamine is of great importance for regulating several eye processes, among which pressure homeostasis is included. Glaucoma, the most prevalent eye disease, also known as the silent thief of vision, is a multifactorial pathology that is associated to age and, often, to intraocular hypertension (IOP). Indeed IOP is the only modifiable risk factor and as such medications are available to control it; however, novel medications are sought to minimize undesirable side effects. Melatonin and analogues decrease IOP in both normotensive and hypertensive eyes. Melatonin activates its cognate membrane receptors, MT1 and MT2, which are present in numerous ocular tissues, including the aqueous-humor-producing ciliary processes. Melatonin receptors belong to the superfamily of G-protein-coupled receptors and their activation would lead to different signalling pathways depending on the tissue. This review describes the molecular mechanisms underlying differential functionalities that are attributed to melatonin receptors. Accordingly, the current work highlights the important role of melatonin and its analogues in the healthy and in the glaucomatous eyes, with special attention to the control of intraocular pressure.
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Affiliation(s)
- Hanan Awad Alkozi
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain
| | - Gemma Navarro
- Centro de Investigación en Red, Enfermedades Neurodegeneratives (CiberNed), Instituto de Salud Carlos III, Sinesio Delgado 6, 28029, Madrid, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Avda. Juan XXIII, 27, 08027, Barcelona, Spain
| | - Rafael Franco
- Centro de Investigación en Red, Enfermedades Neurodegeneratives (CiberNed), Instituto de Salud Carlos III, Sinesio Delgado 6, 28029, Madrid, Spain; Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Diagonal 643, 08028, Barcelona, Barcelona, Spain.
| | - Jesus Pintor
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain; Real Academia Nacional de Farmacia, Calle Farmacia 11, 28004, Madrid, Spain.
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Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives. Pharmacol Res 2019; 144:343-356. [DOI: 10.1016/j.phrs.2019.04.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 03/06/2019] [Accepted: 04/11/2019] [Indexed: 12/15/2022]
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Moreno E, Cavic M, Krivokuca A, Casadó V, Canela E. The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet? Front Pharmacol 2019; 10:339. [PMID: 31024307 PMCID: PMC6459931 DOI: 10.3389/fphar.2019.00339] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare. CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.
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Affiliation(s)
- Estefanía Moreno
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Milena Cavic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Ana Krivokuca
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Vicent Casadó
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Enric Canela
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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Cortés A, Casadó-Anguera V, Moreno E, Casadó V. The heterotetrameric structure of the adenosine A 1-dopamine D 1 receptor complex: Pharmacological implication for restless legs syndrome. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 84:37-78. [PMID: 31229177 DOI: 10.1016/bs.apha.2019.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR-D2R and A1R-D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor-receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R-D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R-D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).
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Affiliation(s)
- Antoni Cortés
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Verònica Casadó-Anguera
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Estefanía Moreno
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Vicent Casadó
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.
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Karamitri A, Sadek MS, Journé AS, Gbahou F, Gerbier R, Osman MB, Habib SAM, Jockers R, Zlotos DP. O-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors. Bioorg Chem 2019; 85:349-356. [PMID: 30658234 DOI: 10.1016/j.bioorg.2019.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 12/17/2022]
Abstract
A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16-24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[125-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and β-arrestin recruitment assays at MT1 and MT2 receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT1 dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors. Bivalent ligands 3c and 7 exhibited important changes in functional properties on the Gi/cAMP pathway but not on the β-arrestin pathway compared to their monomeric counterparts. Interestingly, 3c (20 atoms spacer) shows inverse agonistic properties at MT2 on the Gi/cAMP pathway. In conclusion, these findings indicate that O-linked melatonin dimers are promising tools to develop signaling pathway-based bivalent melatonin receptor ligands.
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Affiliation(s)
- Angeliki Karamitri
- Inserm, U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France
| | - Mirna S Sadek
- The German University in Cairo, Department of Pharmaceutical Chemistry, New Cairo City, 11835 Cairo, Egypt.
| | - Anne-Sophie Journé
- Inserm, U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France
| | - Florence Gbahou
- Inserm, U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France.
| | - Romain Gerbier
- Inserm, U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France
| | - Mai B Osman
- The German University in Cairo, Department of Pharmaceutical Chemistry, New Cairo City, 11835 Cairo, Egypt
| | - Samy A M Habib
- The German University in Cairo, Department of Pharmaceutical Chemistry, New Cairo City, 11835 Cairo, Egypt
| | - Ralf Jockers
- Inserm, U1016, Institut Cochin, Paris, France; CNRS UMR 8104, Paris, France; Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France.
| | - Darius P Zlotos
- The German University in Cairo, Department of Pharmaceutical Chemistry, New Cairo City, 11835 Cairo, Egypt.
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Benleulmi-Chaachoua A, Hegron A, Le Boulch M, Karamitri A, Wierzbicka M, Wong V, Stagljar I, Delagrange P, Ahmad R, Jockers R. Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure. Cell Mol Life Sci 2018; 75:4357-4370. [PMID: 30043140 PMCID: PMC11105639 DOI: 10.1007/s00018-018-2876-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 06/26/2018] [Accepted: 07/16/2018] [Indexed: 12/11/2022]
Abstract
Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT1 and MT2 receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT1 or MT2 receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT1 and MT2) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice.
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MESH Headings
- Animals
- Cell Membrane/metabolism
- Corpus Striatum/metabolism
- Dopamine/metabolism
- Dopamine Plasma Membrane Transport Proteins/genetics
- Dopamine Plasma Membrane Transport Proteins/metabolism
- HEK293 Cells
- Humans
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Motor Activity/genetics
- Protein Binding
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Synaptosomes/metabolism
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Affiliation(s)
- Abla Benleulmi-Chaachoua
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France
| | - Alan Hegron
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France
| | - Marine Le Boulch
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France
| | - Angeliki Karamitri
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France
| | - Marta Wierzbicka
- Donnelly Centre, Department of Biochemistry, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
- Department of Molecular Genetics, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
| | - Victoria Wong
- Donnelly Centre, Department of Biochemistry, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
- Department of Molecular Genetics, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
| | - Igor Stagljar
- Donnelly Centre, Department of Biochemistry, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
- Department of Molecular Genetics, Faculty of Medicine, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
| | - Philippe Delagrange
- Pôle d'Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Servier, 125 Chemin de Ronde, 78290, Croissy, France
| | - Raise Ahmad
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France
| | - Ralf Jockers
- Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France.
- CNRS, UMR 8104, 22 Rue Mechain, 75014, Paris, France.
- University of Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006, Paris, France.
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Casadó-Anguera V, Moreno E, Mallol J, Ferré S, Canela EI, Cortés A, Casadó V. Reinterpreting anomalous competitive binding experiments within G protein-coupled receptor homodimers using a dimer receptor model. Pharmacol Res 2018; 139:337-347. [PMID: 30472462 DOI: 10.1016/j.phrs.2018.11.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 11/14/2018] [Accepted: 11/21/2018] [Indexed: 12/01/2022]
Abstract
An increasing number of G protein-coupled receptors (GPCRs) have been reported to be expressed in the plasma membrane as dimers. Since most ligand binding data are currently fitted by classical equations developed only for monomeric receptors, the interpretation of data could be misleading in the presence of GPCR dimers. On the other hand, the equations developed from dimer receptor models assuming the existence of two orthosteric binding sites within the dimeric molecule offer the possibility to directly calculate macroscopic equilibrium dissociation constants for the two sites, an index of cooperativity (DC) that reflects the molecular communication within the dimer and, importantly, a constant of radioligand-competitor allosteric interaction (KDAB) in competitive assays. Here, we provide a practical way to fit competitive binding data that allows the interpretation of apparently anomalous results, such as competition curves that could be either bell-shaped, monophasic or biphasic depending on the assay conditions. The consideration of a radioligand-competitor allosteric interaction allows fitting these curve patterns both under simulation conditions and in real radioligand binding experiments, obtaining competitor affinity parameters closer to the actual values. Our approach is the first that, assuming the formation of receptor homodimers, is able to explain several experimental results previously considered erroneous due to their impossibility to be fitted. We also deduce the radioligand concentration responsible for the conversion of biphasic to monophasic or to bell-shaped curves in competitive radioligand binding assays. In conclusion, bell-shaped curves in competitive binding experiments constitute evidence for GPCR homodimerization.
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Affiliation(s)
- Verònica Casadó-Anguera
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
| | - Estefanía Moreno
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
| | - Josefa Mallol
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
| | - Sergi Ferré
- National Institute on Drug Abuse, I.R.P., N.I.H., D.H.H.S., Baltimore, MD, 21224, USA.
| | - Enric I Canela
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
| | - Antoni Cortés
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
| | - Vicent Casadó
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
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Clement N, Renault N, Guillaume J, Cecon E, Journé A, Laurent X, Tadagaki K, Cogé F, Gohier A, Delagrange P, Chavatte P, Jockers R. Importance of the second extracellular loop for melatonin MT 1 receptor function and absence of melatonin binding in GPR50. Br J Pharmacol 2018; 175:3281-3297. [PMID: 28898928 PMCID: PMC6057912 DOI: 10.1111/bph.14029] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/09/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Recent crystal structures of GPCRs have emphasized the previously unappreciated role of the second extracellular (E2) loop in ligand binding and gating and receptor activation. Here, we have assessed the role of the E2 loop in the activation of the melatonin MT1 receptor and in the inactivation of the closely related orphan receptor GPR50. EXPERIMENTAL APPROACH Chimeric MT1 -GPR50 receptors were generated and functionally analysed in terms of 2-[125 I]iodomelatonin binding, Gi /cAMP signalling and β-arrestin2 recruitment. We also used computational molecular dynamics (MD) simulations. KEY RESULTS MD simulations of 300 ns revealed (i) the tight hairpin structure of the E2 loop of the MT1 receptor (ii) the most suitable features for melatonin binding in MT1 receptors and (iii) major predicted rearrangements upon MT1 receptor activation, stabilizing interaction networks between Phe179 or Gln181 in the E2 loop and transmembrane helixes 5 and 6. Functional assays confirmed these predictions, because reciprocal replacement of MT1 and GPR50 residues/domains led to the predicted loss- and gain-of-melatonin action of MT1 receptors and GPR50 respectively. CONCLUSIONS AND IMPLICATIONS Our work demonstrated the crucial role of the E2 loop for MT1 receptor and GPR50 function by proposing a model in which the E2 loop is important in stabilizing active MT1 receptor conformations and by showing how evolutionary processes appear to have selected for modifications in the E2 loop in order to make GPR50 unresponsive to melatonin. LINKED ARTICLES This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.
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Affiliation(s)
- Nathalie Clement
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Nicolas Renault
- Univ. Lille, Inserm, CHU Lille, U995 – LIRIC – Lille Inflammation Research International CenterLilleFrance
| | - Jean‐Luc Guillaume
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Erika Cecon
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Anne‐Sophie Journé
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Xavier Laurent
- Univ. Lille, Inserm, CHU Lille, U995 – LIRIC – Lille Inflammation Research International CenterLilleFrance
| | - Kenjiro Tadagaki
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Francis Cogé
- Pôle d'Innovation Thérapeutique NeuropsychiatrieInstitut de Recherches SERVIERCroissy/SeineFrance
| | - Arnaud Gohier
- Pôle d'Innovation Thérapeutique NeuropsychiatrieInstitut de Recherches SERVIERCroissy/SeineFrance
| | - Philippe Delagrange
- Pôle d'Innovation Thérapeutique NeuropsychiatrieInstitut de Recherches SERVIERCroissy/SeineFrance
| | - Philippe Chavatte
- Univ. Lille, Inserm, CHU Lille, U995 – LIRIC – Lille Inflammation Research International CenterLilleFrance
| | - Ralf Jockers
- Inserm, U1016, Institut CochinParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
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Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 2018; 175:3263-3280. [PMID: 28707298 PMCID: PMC6057902 DOI: 10.1111/bph.13950] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 07/05/2017] [Accepted: 07/10/2017] [Indexed: 12/15/2022] Open
Abstract
Melatonin, N-acetyl-5-methoxytryptamine, an evolutionally old molecule, is produced by the pineal gland in vertebrates, and it binds with high affinity to melatonin receptors, which are members of the GPCR family. Among the multiple effects attributed to melatonin, we will focus here on those that are dependent on the activation of the two mammalian MT1 and MT2 melatonin receptors. We briefly summarize the latest developments on synthetic melatonin receptor ligands, including multi-target-directed ligands, and the characterization of signalling-biased ligands. We discuss signalling pathways activated by melatonin receptors that appear to be highly cell- and tissue-dependent, emphasizing the impact of system bias on the functional outcome. Different proteins have been demonstrated to interact with melatonin receptors, and thus, we postulate that part of this system bias has its molecular basis in differences of the expression of receptor-associated proteins including heterodimerization partners. Finally, bias at the level of the receptor, by the expression of genetic receptor variants, will be discussed to show how a modified receptor function can have an effect on the risk for common diseases like type 2 diabetes in humans. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.
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Affiliation(s)
- Erika Cecon
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Atsuro Oishi
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
| | - Ralf Jockers
- Institut CochinInserm, U1016ParisFrance
- CNRS UMR 8104ParisFrance
- Univ. Paris Descartes, Sorbonne Paris CitéParisFrance
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Porzionato A, Stocco E, Guidolin D, Agnati L, Macchi V, De Caro R. Receptor-Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis. Front Physiol 2018; 9:697. [PMID: 29930516 PMCID: PMC6000251 DOI: 10.3389/fphys.2018.00697] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 05/18/2018] [Indexed: 12/15/2022] Open
Abstract
In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs). In other transfected or native cells, GPCRs have been demonstrated to establish physical receptor–receptor interactions (RRIs) with formation of homo/hetero-complexes (dimers or receptor mosaics) in a dynamic monomer/oligomer equilibrium. RRIs modulate ligand binding, signaling, and internalization of GPCR protomers and they are considered of relevance for physiology, pharmacology, and pathology of the nervous system. We hypothesize that RRI may also occur in the different structural elements of the CB (type I cells, type II cells, and afferent fibers), with potential implications in chemoreception, neuromodulation, and tissue plasticity. This ‘working hypothesis’ is supported by literature data reporting the contemporary expression, in type I cells, type II cells, or afferent terminals, of GPCRs which are able to physically interact with each other to form homo/hetero-complexes. Functional data about cross-talks in the CB between different neurotransmitters/neuromodulators also support the hypothesis. On the basis of the above findings, the most significant homo/hetero-complexes which could be postulated in the CB include receptors for dopamine, adenosine, ATP, opioids, histamine, serotonin, endothelin, galanin, GABA, cannabinoids, angiotensin, neurotensin, and melatonin. From a methodological point of view, future studies should demonstrate the colocalization in close proximity (less than 10 nm) of the above receptors, through biophysical (i.e., bioluminescence/fluorescence resonance energy transfer, protein-fragment complementation assay, total internal reflection fluorescence microscopy, fluorescence correlation spectroscopy and photoactivated localization microscopy, X-ray crystallography) or biochemical (co-immunoprecipitation, in situ proximity ligation assay) methods. Moreover, functional approaches will be able to show if ligand binding to one receptor produces changes in the biochemical characteristics (ligand recognition, decoding, and trafficking processes) of the other(s). Plasticity aspects would be also of interest, as development and environmental stimuli (chronic continuous or intermittent hypoxia) produce changes in the expression of certain receptors which could potentially invest the dynamic monomer/oligomer equilibrium of homo/hetero-complexes and the correlated functional implications.
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Affiliation(s)
| | - Elena Stocco
- Department of Neuroscience, University of Padua, Padua, Italy
| | - Diego Guidolin
- Department of Neuroscience, University of Padua, Padua, Italy
| | - Luigi Agnati
- Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Veronica Macchi
- Department of Neuroscience, University of Padua, Padua, Italy
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Zhang Y, Liu Y, Wu L, Fan C, Wang Z, Zhang X, Alachkar A, Liang X, Civelli O. Receptor-specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3. FASEB J 2018; 32:3184-3192. [PMID: 29401613 DOI: 10.1096/fj.201700337rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Bombesin receptor subtype 3 (BRS-3) is a GPCR that is expressed in the CNS, peripheral tissues, and tumors. Our understanding of BRS-3's role in physiology and pathophysiology is limited because its natural ligand is unknown. In an attempt to identify this ligand, we screened toad skin ( Bufo bufo gargarizans Cantor) extracts and identified prostaglandins as putative ligands. In BRS-3-transfected human embryonic kidney (HEK) cells, we found that prostaglandins, with prostaglandin E2 (PGE2) being the most potent, fulfill the pharmacologic criteria of affinity, selectivity, and specificity to be considered as agonists to the BRS-3 receptor. However, PGE2 is unable to activate BRS-3 in different cellular environments. We speculated that EP receptors might be the cause of this cellular selectivity, and we found that EP3 is the receptor primarily responsible for the differential PGE2 effect. Consequently, we reconstituted the HEK environment in Chinese hamster ovary (CHO) cells and found that BRS-3 and EP3 interact to potentiate PGE2 signaling. This potentiating effect is receptor specific, and it occurs only when BRS-3 is paired to EP3. Our study represents an example of functional crosstalk between two distantly related GPCRs and may be of clinical importance for BRS-3-targeted therapies.-Zhang, Y., Liu, Y., Wu, L., Fan, C., Wang, Z., Zhang, X., Alachkar, A., Liang, X., Civelli, O. Receptor-specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3.
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Affiliation(s)
- Yan Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yanfang Liu
- Key Laboratory of Separation Science for Analytical Chemistry, Key Lab of Natural Medicine, Liaoning Province, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Lehao Wu
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Chao Fan
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiwei Wang
- Department of Pharmacology, University of California, Irvine, Irvine, California, USA
| | - Xiuli Zhang
- Key Laboratory of Separation Science for Analytical Chemistry, Key Lab of Natural Medicine, Liaoning Province, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Amal Alachkar
- Department of Pharmacology, University of California, Irvine, Irvine, California, USA
| | - Xinmiao Liang
- Key Laboratory of Separation Science for Analytical Chemistry, Key Lab of Natural Medicine, Liaoning Province, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Olivier Civelli
- Department of Pharmacology, University of California, Irvine, Irvine, California, USA
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Oishi A, Cecon E, Jockers R. Melatonin Receptor Signaling: Impact of Receptor Oligomerization on Receptor Function. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 338:59-77. [DOI: 10.1016/bs.ircmb.2018.02.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R. Melatonin transport into mitochondria. Cell Mol Life Sci 2017; 74:3927-3940. [PMID: 28828619 PMCID: PMC11107582 DOI: 10.1007/s00018-017-2616-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/03/2017] [Indexed: 12/15/2022]
Abstract
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole's protective actions. Melatonin's mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.
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Affiliation(s)
- Juan C Mayo
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain.
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
| | - Rosa M Sainz
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Pedro González-Menéndez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - David Hevia
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Rafael Cernuda-Cernuda
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
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Chuffa LGDA, Reiter RJ, Lupi LA. Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. Carcinogenesis 2017; 38:945-952. [PMID: 28575150 DOI: 10.1093/carcin/bgx054] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 06/01/2017] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti-proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment.
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Affiliation(s)
- Luiz Gustavo de Almeida Chuffa
- Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu-SP, Brazil and Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA
| | - Russel J Reiter
- Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu-SP, Brazil and Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA
| | - Luiz Antonio Lupi
- Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista, Botucatu-SP, Brazil and Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA
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Gbahou F, Cecon E, Viault G, Gerbier R, Jean-Alphonse F, Karamitri A, Guillaumet G, Delagrange P, Friedlander RM, Vilardaga JP, Suzenet F, Jockers R. Design and validation of the first cell-impermeant melatonin receptor agonist. Br J Pharmacol 2017; 174:2409-2421. [PMID: 28493341 DOI: 10.1111/bph.13856] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/27/2017] [Accepted: 05/03/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT1 and MT2 receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools. EXPERIMENTAL APPROACH We therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy. KEY RESULTS Among the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT1 and MT2 receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the Gi /cAMP and ERK pathway and β-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between Gi /cAMP signalling of the MT1 receptor initiated at the cell surface and neuronal mitochondria. CONCLUSIONS AND IMPLICATIONS We report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT1 receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.
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Affiliation(s)
- Florence Gbahou
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,Université Paris Descartes, Paris, France
| | - Erika Cecon
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,Université Paris Descartes, Paris, France
| | - Guillaume Viault
- Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, B.P. 6759, Orléans Cedex 2, France
| | - Romain Gerbier
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,Université Paris Descartes, Paris, France
| | - Frederic Jean-Alphonse
- Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Angeliki Karamitri
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,Université Paris Descartes, Paris, France
| | - Gérald Guillaumet
- Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, B.P. 6759, Orléans Cedex 2, France
| | - Philippe Delagrange
- Pôle d'Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Servier, Croissy, France
| | - Robert M Friedlander
- Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jean-Pierre Vilardaga
- Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Franck Suzenet
- Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, B.P. 6759, Orléans Cedex 2, France
| | - Ralf Jockers
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,Université Paris Descartes, Paris, France
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49
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González-Arto M, Aguilar D, Gaspar-Torrubia E, Gallego M, Carvajal-Serna M, Herrera-Marcos LV, Serrano-Blesa E, Hamilton TRDS, Pérez-Pé R, Muiño-Blanco T, Cebrián-Pérez JA, Casao A. Melatonin MT₁ and MT₂ Receptors in the Ram Reproductive Tract. Int J Mol Sci 2017; 18:ijms18030662. [PMID: 28335493 PMCID: PMC5372674 DOI: 10.3390/ijms18030662] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/10/2017] [Accepted: 03/15/2017] [Indexed: 12/15/2022] Open
Abstract
Some melatonin functions in mammals are exerted through MT1 and MT2 receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, accessory glands and ductus deferens. Real-time polymerase chain reaction (qPCR) revealed higher levels of m-RNA for both receptors in the testis, ampulla, seminal vesicles, and vas deferens, than in the other organs of the reproductive tract (p < 0.05). Western blot analyses showed protein bands compatible with the MT1 in the testis and cauda epididymis, and for the MT2 in the cauda epididymis and deferent duct. Immunohistochemistry analyses revealed the presence of MT1 receptors in spermatogonias, spermatocytes, and spermatids, and MT2 receptors in the newly-formed spermatozoa in the testis, whereas both receptors were located in the epithelial cells of the ampulla, seminal vesicles, and ductus deferens. Indirect immunofluorescence showed significant differences in the immunolocation of both receptors in spermatozoa during their transit in the epididymis. In conclusion, it was demonstrated that melatonin receptors are present in the ram reproductive tract. These results open the way for new studies on the molecular mechanism of melatonin and the biological significance of its receptors.
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Affiliation(s)
- Marta González-Arto
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - David Aguilar
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Elena Gaspar-Torrubia
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Margarita Gallego
- Departamento de Patología Animal, Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Melissa Carvajal-Serna
- Departamento de Producción Animal, Facultad de Medicina Veterinaria y de Zootecnia, Universidad Nacional de Colombia, 11001 Bogotá, Colombia.
| | - Luis V Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Edith Serrano-Blesa
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Thais Rose Dos Santos Hamilton
- Dpto. de Reprodução Animal, da Faculdade de Medicina Veterinaria e Zootecnia, da Universidade de São Paulo, 05508 270 São Paulo, Brazil.
| | - Rosaura Pérez-Pé
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Teresa Muiño-Blanco
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - José A Cebrián-Pérez
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
| | - Adriana Casao
- Grupo Biología y Fisiología de la Reproducción, Instituto de Investigación de Ciencias Ambientales de Aragón (IUCA), Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
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50
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Liu J, Clough SJ, Dubocovich ML. Role of the MT1and MT2melatonin receptors in mediating depressive- and anxiety-like behaviors in C3H/HeN mice. GENES BRAIN AND BEHAVIOR 2017; 16:546-553. [DOI: 10.1111/gbb.12369] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 12/20/2016] [Accepted: 01/23/2017] [Indexed: 12/29/2022]
Affiliation(s)
- J. Liu
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences; University at Buffalo (SUNY); Buffalo NY USA
| | - S. J. Clough
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences; University at Buffalo (SUNY); Buffalo NY USA
| | - M. L. Dubocovich
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences; University at Buffalo (SUNY); Buffalo NY USA
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