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Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II. Molecules 2022; 27:molecules27103140. [PMID: 35630616 PMCID: PMC9143373 DOI: 10.3390/molecules27103140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 11/16/2022] Open
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Profiling novel pharmacology of receptor complexes using Receptor-HIT. Biochem Soc Trans 2021; 49:1555-1565. [PMID: 34436548 PMCID: PMC8421044 DOI: 10.1042/bst20201110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 02/07/2023]
Abstract
Many receptors are able to undergo heteromerisation, leading to the formation of receptor complexes that may have pharmacological profiles distinct from those of the individual receptors. As a consequence of this, receptor heteromers can be classed as new drug targets, with the potential for achieving greater specificity and selectivity over targeting their constituent receptors. We have developed the Receptor-Heteromer Investigation Technology (Receptor-HIT), which enables the detection of receptor heteromers using a proximity-based reporter system such as bioluminescence resonance energy transfer (BRET). Receptor-HIT detects heteromers in live cells and in real time, by utilising ligand-induced signals that arise from altered interactions with specific biomolecules, such as ligands or proteins. Furthermore, monitoring the interaction between the receptors and the specific biomolecules generates functional information about the heteromer that can be pharmacologically quantified. This review will discuss various applications of Receptor-HIT, including its use with different classes of receptors (e.g. G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and others), its use to monitor receptor interactions both intracellularly and extracellularly, and also its use with genome-edited endogenous proteins.
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Ko MJ, Ganzen LC, Coskun E, Mukadam AA, Leung YF, van Rijn RM. A critical evaluation of TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-nociceptive drug discovery. Sci Rep 2019; 9:2430. [PMID: 30787340 PMCID: PMC6382835 DOI: 10.1038/s41598-019-38852-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 01/11/2019] [Indexed: 12/12/2022] Open
Abstract
Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
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Affiliation(s)
- Mee Jung Ko
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, USA
- Purdue Institute for Integrative Neuroscience, West Lafayette, USA
- Purdue Interdisciplinary Life Sciences Graduate Program, West Lafayette, USA
| | - Logan C Ganzen
- Department of Biological Sciences, College of Science, West Lafayette, USA
- Purdue Institute for Integrative Neuroscience, West Lafayette, USA
- Purdue Interdisciplinary Life Sciences Graduate Program, West Lafayette, USA
| | - Emre Coskun
- Department of Biological Sciences, College of Science, West Lafayette, USA
| | - Arbaaz A Mukadam
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, USA
| | - Yuk Fai Leung
- Department of Biological Sciences, College of Science, West Lafayette, USA
- Purdue Institute for Integrative Neuroscience, West Lafayette, USA
- Purdue Interdisciplinary Life Sciences Graduate Program, West Lafayette, USA
- Purdue Institute for Drug Discovery, West Lafayette, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, West Lafayette, IN, 47907, USA
| | - Richard M van Rijn
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, USA.
- Purdue Institute for Integrative Neuroscience, West Lafayette, USA.
- Purdue Interdisciplinary Life Sciences Graduate Program, West Lafayette, USA.
- Purdue Institute for Drug Discovery, West Lafayette, USA.
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Haass-Koffler CL. The corticotropin releasing factor binding protein: A strange case of Dr. Jekyll and Mr. Hyde in the stress system? Alcohol 2018; 72:3-8. [PMID: 29510883 DOI: 10.1016/j.alcohol.2017.10.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 09/19/2017] [Accepted: 10/06/2017] [Indexed: 11/28/2022]
Abstract
The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP). Extensive literature suggests a role of CRF in alcohol use disorder (AUD). Less is known about the specific role, if any, of CRFBP in AUD. In this review, we summarize recent interdisciplinary efforts toward identifying the contribution of CRFBP in mediating CRF activation. The role of CRFBP in alcohol-related behaviors has been evaluated with the ultimate goal of designing effective novel therapeutic strategies for AUD. A series of in vitro, in vivo, ex vivo, and genetic studies presented here provides initial evidence that CRFBP may possess both inhibitory and excitatory roles, and supports the original hypothesis that it represents a novel pharmacological target for the treatment of AUD. This report summarizes the proceedings of one of the talks at the Young Investigator Award symposium at the Alcoholism and Stress: A Framework for Future Treatment Strategies Conference, Volterra, Italy.
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Affiliation(s)
- Carolina L Haass-Koffler
- Center for Alcohol and Addiction Studies, Department of Psychiatry and Human Behavior, Department of Behavioral and Social Sciences, 121 South Main Street, Brown University, Providence, RI 02919, USA; Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA and NIDA, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
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Márquez-Gómez R, Robins MT, Gutiérrez-Rodelo C, Arias JM, Olivares-Reyes JA, van Rijn RM, Arias-Montaño JA. Functional histamine H 3 and adenosine A 2A receptor heteromers in recombinant cells and rat striatum. Pharmacol Res 2018; 129:515-525. [PMID: 29217157 PMCID: PMC6429923 DOI: 10.1016/j.phrs.2017.11.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/23/2017] [Accepted: 11/30/2017] [Indexed: 01/02/2023]
Abstract
In the striatum, histamine H3 receptors (H3Rs) are co-expressed with adenosine A2A receptors (A2ARs) in the cortico-striatal glutamatergic afferents and the GABAergic medium-sized spiny neurons that originate the indirect pathway of the basal ganglia. This location allows H3Rs and A2ARs to regulate the striatal GABAergic and glutamatergic transmission. However, whether these receptors can physically interact has not yet been assessed. To test this hypothesis, a heteromer-selective in vitro assay was used to detect functional complementation between a chimeric A2AR302-Gαqi4 and wild-type H3Rs in transfected HEK-293T cells. H3R activation with the agonist RAMH resulted in Ca2+ mobilization (pEC50 7.31 ± 0.23; maximal stimulation, Emax 449 ± 25% of basal) indicative of receptor heterodimerization. Functional H3R-A2AR heteromers were confirmed by co-immunoprecipitation and observations of differential cAMP signaling when both receptors were co-expressed in the same cells. In membranes from rat striatal synaptosomes, H3R activation decreased A2AR affinity for the agonist CGS-21680 (pKi values 8.10 ± 0.04 and 7.70 ± 0.04). Moreover, H3Rs and A2ARs co-immunoprecipitated in protein extracts from striatal synaptosomes. These results support the existence of a H3R-A2AR heteromer with possible physiological implications for the modulation of the intra-striatal transmission.
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Affiliation(s)
- Ricardo Márquez-Gómez
- Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico.
| | - Meridith T Robins
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, USA
| | - Citlaly Gutiérrez-Rodelo
- Departamento de Bioquímica, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
| | - Juan-Manuel Arias
- Programa de Neurociencias-UIICSE, Facultad de Estudios Superiores Iztacala, UNAM, Av. de los Barrios 1, Los Reyes Iztacala, 54090 Estado de México, Mexico
| | | | - Richard M van Rijn
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, USA
| | - José-Antonio Arias-Montaño
- Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav-IPN, Av. IPN 2508, Zacatenco, 07360 Ciudad de México, Mexico
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Nieto-Alamilla G, Márquez-Gómez R, García-Gálvez AM, Morales-Figueroa GE, Arias-Montaño JA. The Histamine H3 Receptor: Structure, Pharmacology, and Function. Mol Pharmacol 2016; 90:649-673. [PMID: 27563055 DOI: 10.1124/mol.116.104752] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/24/2016] [Indexed: 01/06/2023] Open
Abstract
Among the four G protein-coupled receptors (H1-H4) identified as mediators of the biologic effects of histamine, the H3 receptor (H3R) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The cloning of the H3R cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work, we review the characteristics of the H3R, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation. The H3R has attracted interest as a potential drug target for the treatment of several important neurologic and psychiatric disorders, such as Alzheimer and Parkinson diseases, Gilles de la Tourette syndrome, and addiction.
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Affiliation(s)
- Gustavo Nieto-Alamilla
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
| | - Ricardo Márquez-Gómez
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
| | - Ana-Maricela García-Gálvez
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
| | - Guadalupe-Elide Morales-Figueroa
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
| | - José-Antonio Arias-Montaño
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Zacatenco, Ciudad de México, México
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Chiang T, Sansuk K, van Rijn RM. β-Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake. Br J Pharmacol 2016; 173:332-43. [PMID: 26507558 DOI: 10.1111/bph.13374] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 09/30/2015] [Accepted: 10/11/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND AND PURPOSE δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β-arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. EXPERIMENTAL APPROACH We used three diarylmethylpiperazine-based non-peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and β-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of β-arrestin 2 in δ receptor pharmacology. KEY RESULTS All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β-arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were β-arrestin 2-dependent. CONCLUSIONS AND IMPLICATIONS Our finding that δ receptor agonists that strongly recruit β-arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders.
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Affiliation(s)
- T Chiang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
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Kilpatrick LE, Humphrys LJ, Holliday ND. A G protein-coupled receptor dimer imaging assay reveals selectively modified pharmacology of neuropeptide Y Y1/Y5 receptor heterodimers. Mol Pharmacol 2015; 87:718-32. [PMID: 25637604 DOI: 10.1124/mol.114.095356] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The ability of G protein-coupled receptors (GPCRs) to form dimers, and particularly heterodimers, offers potential for targeted therapeutics with improved selectivity. However, studying dimer pharmacology is challenging, because of signaling cross-talk or because dimerization may often be transient in nature. Here we develop a system to isolate the pharmacology of precisely defined GPCR dimers, trapped by bimolecular fluorescence complementation (BiFC). Specific effects of agonist activation on such dimers are quantified using automated imaging and analysis of their internalization, controlled for by simultaneous assessment of endocytosis of one coexpressed protomer population. We applied this BiFC system to study example neuropeptide Y (NPY) Y1 receptor dimers. Incorporation of binding-site or phosphorylation-site mutations into just one protomer of a Y1/Y1 BiFC homodimer had no impact on efficient NPY-stimulated endocytosis, demonstrating that single-site agonist occupancy, and one phosphorylated monomer within this dimer, was sufficient. For two Y1 receptor heterodimer combinations (with the Y4 receptor or β2-adrenoceptor), agonist and antagonist pharmacology was explained by independent actions on the respective orthosteric binding sites. However, Y1/Y5 receptor BiFC dimers, compared with the constituent subtypes, were characterized by reduced potency and efficacy of Y5-selective peptide agonists, the inactivity of Y1-selective antagonists, and a change from surmountable to nonsurmountable antagonism for three unrelated Y5 antagonists. Thus, allosteric interactions between Y1 and Y5 receptors modify the pharmacology of the heterodimer, with implications for potential antiobesity agents that target centrally coexpressed Y1 and Y5 receptors to suppress appetite.
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Affiliation(s)
- Laura E Kilpatrick
- School of Life Sciences, University of Nottingham, The Medical School, Queen's Medical Centre, Nottingham, United Kingdom
| | - Laura J Humphrys
- School of Life Sciences, University of Nottingham, The Medical School, Queen's Medical Centre, Nottingham, United Kingdom
| | - Nicholas D Holliday
- School of Life Sciences, University of Nottingham, The Medical School, Queen's Medical Centre, Nottingham, United Kingdom
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Mudgal A, Pasha S. Role of opioid receptor heterodimerization in pain modulation and tolerance development. World J Pharmacol 2015; 4:144-159. [DOI: 10.5497/wjp.v4.i1.144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/09/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their function, particularly in case of G-protein coupled receptors. The opioid receptor heteromers having changed pharmacological properties than the constituent protomers provides preferences for novel drug targets that could lead to potential analgesic activity devoid of tolerance and physical dependence. Heterodimerization of opioid receptors appears to generate novel binding properties with improved specificity and lack of side effects. Further the molecules which can interact simultaneously to both the protomers of the heteromer, or to both the binding sites (orthosteric and allosteric) of a receptor protein could be potential therapeutic molecules. This review highlights the recent advancements in exploring the plausible role of heteromerization of opioid receptors in induction of tolerance free antinociception.
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Abstract
This paper is the thirty-sixth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2013 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, Flushing, NY 11367, United States.
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Adeghate E, Fehér E, Kalász H. Evaluating the Phase II drugs currently under investigation for diabetic neuropathy. Expert Opin Investig Drugs 2014; 24:1-15. [PMID: 25171371 DOI: 10.1517/13543784.2014.954033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction: The worldwide number of patients suffering from diabetes mellitus (DM) is projected to approach 552 million by the year 2030. As diabetic neuropathy (DN) is present in 8% of new diabetic patients at the time of diagnosis and occurs in ∼ 50% of all patients with established DM, the number of patients who will develop painful DN will also increase. The suboptimal efficacies of currently approved drugs have prompted investigators to develop new therapeutic agents for the management of painful DN. Areas covered: In this review, the authors present and elucidate the current status of drugs under investigation for the treatment of painful DN. A short synopsis of currently approved drugs is also given. Literature information and data analysis were retrieved from PubMed, the American Diabetes and Neurological Associations Websites and ClinicalTrials.gov. The keywords used in the search included: DM, DN, painful diabetic neuropathy. Expert opinion: In addition to treating the pain associated with DN, the actual causes of the disease should also be targeted for improved management. It is hoped that drugs which improve vascular blood flow, induce neural regeneration, reduce hyperglycemia, oxidative stress and inflammation can be more effective for the overall treatment of painful DN.
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Affiliation(s)
- Ernest Adeghate
- United Arab Emirates University, College of Medicine and Health Sciences, Department of Anatomy , P.O Box 17666, Al Ain , UAE +971 3 7672033 ;
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Fujita W, Gomes I, Devi LA. Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities. Br J Pharmacol 2014; 172:375-87. [PMID: 24571499 DOI: 10.1111/bph.12663] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/05/2014] [Accepted: 02/17/2014] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
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Affiliation(s)
- Wakako Fujita
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Yoo JH, Bailey A, Borsodi A, Tóth G, Matifas A, Kieffer BL, Kitchen I. Knockout subtraction autoradiography: a novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain. Eur J Pharmacol 2014; 731:1-7. [PMID: 24657279 DOI: 10.1016/j.ejphar.2014.03.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 03/06/2014] [Accepted: 03/10/2014] [Indexed: 10/25/2022]
Abstract
Several methodological approaches suggest that receptor heteromers exist in cell systems, but their presence in physiological tissue is widely contentious. We describe a novel method to determine if heterodimers exist in brain tissue sections using autoradiographic binding comparisons from single and double gene knockout mice, where tissues either have a full receptor complement and can form heterodimers, or are incapable of making heterodimers. We have tested this model, which we have named Knockout Subtraction Autoradiography, to determine if heterodimerisation of the kappa (KOP) and delta opioid (DOP) receptors occurs, as evidence from binding studies in cell systems suggest they are present in the brain. Using labeling of putative KOP receptor/DOP receptor heterodimers with either [(3)H]bremazocine or with [(3)H]naltrindole, two ligands which were used to provide evidence suggesting that these opioid receptor subtypes heterodimerize, we have applied a subtraction equation model based on the principle that receptor gene double knockout of either MOP receptor/KOP receptor (DOP receptor expression only) or MOP receptor/DOP receptor (KOP receptor expression only) produces tissue incapable of making the KOP receptor/DOP receptor heterodimer. We have shown in most brain regions that the labeling fits a simple additive model of monomer labeling, but that in a few brain regions opioid receptor heterodimerization does occur. The data does not support the conclusion that KOP receptor/DOP receptor heterodimerisation is widespread in the central nervous system, but does indicate that this novel methodology can detect heterodimerisation, when ligands with distinct binding affinities for monomer and heterodimer forms exist.
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Affiliation(s)
- Ji-Hoon Yoo
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
| | - Alexis Bailey
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
| | - Anna Borsodi
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, Szeged H-6726, Hungary
| | - Géza Tóth
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, Szeged H-6726, Hungary
| | - Audrey Matifas
- IGBMC, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 10142, Illkirch, Cedex, France
| | - Brigitte L Kieffer
- IGBMC, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 10142, Illkirch, Cedex, France
| | - Ian Kitchen
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
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Ong EW, Cahill CM. Molecular Perspectives for mu/delta Opioid Receptor Heteromers as Distinct, Functional Receptors. Cells 2014; 3:152-79. [PMID: 24709907 PMCID: PMC3980742 DOI: 10.3390/cells3010152] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/14/2014] [Accepted: 02/21/2014] [Indexed: 02/06/2023] Open
Abstract
Opioid receptors are the sites of action for morphine and the other opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Understandings of the nature, behavior, and role of these opioid receptor heteromers are developing. Owing to their constituent monomers’ involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. There is now considerable evidence demonstrating M/DOR to be an extant and physiologically relevant receptor species. Participating in the cellular environment as a distinct receptor type, M/DOR availability is complexly regulated and M/DOR exhibits unique pharmacology from that of other opioid receptors (ORs), including its constituents. M/DOR appears to have a range of actions that vary in a ligand- (or ligands-) dependent manner. These actions can meaningfully affect the clinical effects of opioid drugs: strategies targeting M/DOR may be therapeutically useful. This review presents and discusses developments in these understandings with a focus on the molecular nature and activity of M/DOR in the context of therapeutic potentials.
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Affiliation(s)
- Edmund W Ong
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
| | - Catherine M Cahill
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
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15
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Benleulmi-Chaachoua A, Wojciech S, Jockers R. [G protein-coupled receptors in the spot light]. Biol Aujourdhui 2013; 207:191-200. [PMID: 24330972 DOI: 10.1051/jbio/2013014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Indexed: 06/03/2023]
Abstract
G protein-coupled receptors (GPCRs), also known as seven transmembrane domain-spanning proteins (7TM), play an important role in tissue homeostasis and cellular and hormonal communication. GPCRs are targeted by a large panel of natural ligands such as photons, ions, metabolites, lipids and proteins but also by numerous drugs. Research efforts in the GPCR field have been rewarded in 2012 by the Nobel Price in Chemistry. The present article briefly summarizes our current knowledge on GPCRs and discusses future challenges in terms of fundamental aspects and therapeutic applications.
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Affiliation(s)
- Abla Benleulmi-Chaachoua
- Inserm, U1016, Institut Cochin, 22 rue Méchain, 75014 Paris, France - CNRS UMR 8104, Institut Cochin, 22 rue Méchain, 75014 Paris, France - Université Paris Descartes, 12 rue de l'École de Médecine, 75006 Paris, France
| | - Stefanie Wojciech
- Inserm, U1016, Institut Cochin, 22 rue Méchain, 75014 Paris, France - CNRS UMR 8104, Institut Cochin, 22 rue Méchain, 75014 Paris, France - Université Paris Descartes, 12 rue de l'École de Médecine, 75006 Paris, France
| | - Ralf Jockers
- Inserm, U1016, Institut Cochin, 22 rue Méchain, 75014 Paris, France - CNRS UMR 8104, Institut Cochin, 22 rue Méchain, 75014 Paris, France - Université Paris Descartes, 12 rue de l'École de Médecine, 75006 Paris, France
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Hiller C, Kühhorn J, Gmeiner P. Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands. J Med Chem 2013; 56:6542-59. [DOI: 10.1021/jm4004335] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Christine Hiller
- Department of Chemistry and Pharmacy,
Emil Fischer
Center, Friedrich Alexander University,
Schuhstraße 19, 91052 Erlangen, Germany
| | - Julia Kühhorn
- Department of Chemistry and Pharmacy,
Emil Fischer
Center, Friedrich Alexander University,
Schuhstraße 19, 91052 Erlangen, Germany
| | - Peter Gmeiner
- Department of Chemistry and Pharmacy,
Emil Fischer
Center, Friedrich Alexander University,
Schuhstraße 19, 91052 Erlangen, Germany
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