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Lecce E, Bellini A, Greco G, Martire F, Scotto di Palumbo A, Sacchetti M, Bazzucchi I. Physiological mechanisms of neuromuscular impairment in diabetes-related complications: Can physical exercise help prevent it? J Physiol 2025. [PMID: 39898972 DOI: 10.1113/jp287589] [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: 09/20/2024] [Accepted: 01/14/2025] [Indexed: 02/04/2025] Open
Abstract
Diabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation-reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre-synaptic vesicles, mitochondrial content and post-synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes-related complications are compounded by age-related degenerative changes in long-term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline.
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Affiliation(s)
- Edoardo Lecce
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Alessio Bellini
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Giuseppe Greco
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Fiorella Martire
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Alessandro Scotto di Palumbo
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Massimo Sacchetti
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Ilenia Bazzucchi
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
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Sanner K, Kawell S, Evans JG, Elekovic V, Walz M, Joksimovic SL, Joksimovic SM, Donald RR, Tomic M, Orestes P, Feseha S, Dedek A, Ghodsi SM, Fallon IP, Lee J, Hwang SM, Hong SJ, Mayer JP, Covey DF, Romano C, Timic Stamenic T, Chemin J, Bourinet E, Poulen G, Longon N, Vachiery-Lahaye F, Bauchet L, Zorumski CF, Stowell MHB, Hildebrand ME, Eisenmesser EZ, Jevtovic-Todorovic V, Todorovic SM. Facilitation of Ca V 3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.03.631165. [PMID: 39868306 PMCID: PMC11760774 DOI: 10.1101/2025.01.03.631165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The Ca V 3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability of nociceptive neurons; the endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover a novel peptide albumin (1-26) that facilitates channel gating by chelating trace metals that tonically inhibit Ca V 3.2 via H191 residue. Importantly, serum also potently modulated T-currents in human and rodent dorsal root ganglion (DRG) neurons. In vivo pain studies revealed that injections of serum and albumin (1-26) peptide resulted in robust mechanical and heat hypersensitivity. This hypersensitivity was abolished with a T-channel inhibitor, in Ca V 3.2 null mice and in Ca V 3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of Ca V 3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.
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3
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Huang J, Fan X, Jin X, Lyu C, Guo Q, Liu T, Chen J, Davakan A, Lory P, Yan N. Structural basis for human Ca v3.2 inhibition by selective antagonists. Cell Res 2024; 34:440-450. [PMID: 38605177 PMCID: PMC11143251 DOI: 10.1038/s41422-024-00959-8] [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: 12/21/2023] [Accepted: 04/02/2024] [Indexed: 04/13/2024] Open
Abstract
The Cav3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Cav3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.
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Affiliation(s)
- Jian Huang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Xiao Fan
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
- Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, USA.
| | - Xueqin Jin
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Chen Lyu
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Qinmeng Guo
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Tao Liu
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jiaofeng Chen
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Amaël Davakan
- IGF, Université de Montpellier, CNRS, INSERM, LabEx 'Ion Channel Science and Therapeutics', Montpellier, France
| | - Philippe Lory
- IGF, Université de Montpellier, CNRS, INSERM, LabEx 'Ion Channel Science and Therapeutics', Montpellier, France
| | - Nieng Yan
- Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
- Institute of Bio-Architecture and Bio-Interactions, Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong, China.
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4
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Weiss N, Zamponi GW. The T-type calcium channelosome. Pflugers Arch 2024; 476:163-177. [PMID: 38036777 DOI: 10.1007/s00424-023-02891-z] [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: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.
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Affiliation(s)
- Norbert Weiss
- Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
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5
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Wang Y, Lopez-Bellido R, Huo X, Kavelaars A, Galko MJ. The insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice. Biol Open 2023; 12:bio059864. [PMID: 37259940 PMCID: PMC10245137 DOI: 10.1242/bio.059864] [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: 02/08/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023] Open
Abstract
Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent mechanical hypersensitivity. Mice with a specific deletion of the Insr gene in Nav1.8+ nociceptive sensory neurons showed nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the Nav1.8+ sensory neuron-specific deletion of Insr did not show metabolic abnormalities typical of a defect in systemic insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.
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Affiliation(s)
- Yan Wang
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Roger Lopez-Bellido
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiaojiao Huo
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Annemieke Kavelaars
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Neuroscience Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Michael J. Galko
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Neuroscience Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- Genetics & Epigenetics Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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6
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Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, Tian Y, Fu X. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm (Beijing) 2023; 4:e283. [PMID: 37303813 PMCID: PMC10248034 DOI: 10.1002/mco2.283] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.
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Affiliation(s)
- Rong Cao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Huimin Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yu Zhang
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Geng Liu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Haixia Xu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Guocheng Rao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yan Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Xianghui Fu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
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7
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Jin Y, Mao Y, Chen D, Tai Y, Hu R, Yang CL, Zhou J, Chen L, Liu X, Gu E, Jia C, Zhang Z, Tao W. Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia. J Clin Invest 2022; 132:158742. [PMID: 36519547 PMCID: PMC9754001 DOI: 10.1172/jci158742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 10/18/2022] [Indexed: 12/15/2022] Open
Abstract
Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel-mediated neural circuit basis for RIH that can guide analgesic development.
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Affiliation(s)
- Yan Jin
- Stroke Center and Department of Neurology and,Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Yu Mao
- Stroke Center and Department of Neurology and,Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Danyang Chen
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Yingju Tai
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Rui Hu
- Department of Anesthesiology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chen-Ling Yang
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Jing Zhou
- Department of head, neck, and breast Surgery, Western district of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Lijian Chen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xuesheng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Erwei Gu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chunhui Jia
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Zhi Zhang
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC, Hefei, China
| | - Wenjuan Tao
- Stroke Center and Department of Neurology and,Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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8
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Maskin SL. Successful reversal of neuropathic eye pain by treatment of occult ocular surface disease: Case series and implications. Am J Ophthalmol Case Rep 2022; 27:101662. [PMID: 35873369 PMCID: PMC9301504 DOI: 10.1016/j.ajoc.2022.101662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/25/2022] [Accepted: 07/10/2022] [Indexed: 12/05/2022] Open
Abstract
Purpose To report the successful approach to managing neuropathic dry eye-like pain (NP) in three consecutive patients described as severe: 1) “burning fire,” “burning acid,” and “horrible burning pain” with hyperalgesia and allodynia, 2) refractory to topical anesthetic (TA), and 3) without surface hyperemia nor vital staining. Observations Two of three patients' pain was reversed with significant symptom relief within 48 hours by identification of occult obstructive Meibomian gland dysfunction (o-MGD) and treatment using Meibomian gland probing (MGP) with intraductal steroid lavage (MGP(s)) and aqueous tear deficiency (ATD) treated with punctal thermocautery (PO). The third patient's pain was reversed within one week after treatment of superior conjunctivochalasis (CCh) using amniotic membrane surface reconstruction and ATD using PO with subsequent MGP and MGP(s) for o-MGD. Conclusions and importance It has been generally thought that central (NP) is strongly suggested by triad of 1) severe chronic burning pain with hyperalgesia and allodynia, 2) refractory to TA with 3) minimal signs. In this three-case series, treatment of occult surface disease consistently led to symptom reversal. Results may represent salutary effect of successful treatment to suppress nociceptive inflammation leading to reversal of central NP. Alternatively, the current triad of diagnostic criteria may be unable to differentiate centralized NP from peripheral sensitization alone, thereby requiring rigorous examination to uncover occult, yet treatable, surface disease to restore eye comfort and reverse psychosocial sequelae when possible. Furthermore, rigorous targeting of surface disease in patients with this pain triad may obviate unnecessary systemic treatments with associated risks of serious side effects.
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9
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Fang XX, Wang H, Song HL, Wang J, Zhang ZJ. Neuroinflammation Involved in Diabetes-Related Pain and Itch. Front Pharmacol 2022; 13:921612. [PMID: 35795572 PMCID: PMC9251344 DOI: 10.3389/fphar.2022.921612] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.
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Affiliation(s)
- Xiao-Xia Fang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
- Department of Medical Functional Laboratory, School of Medicine, Nantong University, Nantong, China
| | - Heng Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Hao-Lin Song
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Juan Wang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
| | - Zhi-Jun Zhang
- Department of Human Anatomy, School of Medicine, Nantong University, Nantong, China
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10
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Harding EK, Zamponi GW. Central and peripheral contributions of T-type calcium channels in pain. Mol Brain 2022; 15:39. [PMID: 35501819 PMCID: PMC9063214 DOI: 10.1186/s13041-022-00923-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/13/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractChronic pain is a severely debilitating condition that reflects a long-term sensitization of signal transduction in the afferent pain pathway. Among the key players in this pathway are T-type calcium channels, in particular the Cav3.2 isoform. Because of their biophysical characteristics, these channels are ideally suited towards regulating neuronal excitability. Recent evidence suggests that T-type channels contribute to excitability of neurons all along the ascending and descending pain pathways, within primary afferent neurons, spinal dorsal horn neurons, and within pain-processing neurons in the midbrain and cortex. Here we review the contribution of T-type channels to neuronal excitability and function in each of these neuronal populations and how they are dysregulated in chronic pain conditions. Finally, we discuss their molecular pharmacology and the potential role of these channels as therapeutic targets for chronic pain.
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11
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Joksimovic SL, Jevtovic-Todorovic V, Todorovic SM. The Mechanisms of Plasticity of Nociceptive Ion Channels in Painful Diabetic Neuropathy. FRONTIERS IN PAIN RESEARCH 2022; 3:869735. [PMID: 35419564 PMCID: PMC8995507 DOI: 10.3389/fpain.2022.869735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Treating pain in patients suffering from small fiber neuropathies still represents a therapeutic challenge for health care providers and drug developers worldwide. Unfortunately, none of the currently available treatments can completely reverse symptoms of either gain or loss of peripheral nerve sensation. Therefore, there is a clear need for novel mechanism-based therapies for peripheral diabetic neuropathy (PDN) that would improve treatment of this serious condition. In this review, we summarize the current knowledge on the mechanisms and causes of peripheral sensory neurons damage in diabetes. In particular, we focused on the subsets of voltage-gated sodium channels, TRP family of ion channels and a CaV3.2 isoform of T-type voltage-gated calcium channels. However, even though their potential is well-validated in multiple rodent models of painful PDN, clinical trials with specific pharmacological blockers of these channels have failed to exhibit therapeutic efficacy. We argue that understanding the development of diabetes and causal relationship between hyperglycemia, glycosylation, and other post-translational modifications may lead to the development of novel therapeutics that would efficiently alleviate painful PDN by targeting disease-specific mechanisms rather than individual nociceptive ion channels.
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Affiliation(s)
- Sonja L Joksimovic
- Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States
| | | | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States
- Neuroscience Graduate Program, University of Colorado Denver, Aurora, CO, United States
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12
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Voltage-dependent Ca V3.2 and Ca V2.2 channels in nociceptive pathways. Pflugers Arch 2022; 474:421-434. [PMID: 35043234 DOI: 10.1007/s00424-022-02666-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 10/19/2022]
Abstract
Noxious stimuli like cold, heat, pH change, tissue damage, and inflammation depolarize a membrane of peripheral endings of specialized nociceptive neurons which eventually results in the generation of an action potential. The electrical signal is carried along a long axon of nociceptive neurons from peripheral organs to soma located in dorsal root ganglions and further to the dorsal horn of the spinal cord where it is transmitted through a chemical synapse and is carried through the spinal thalamic tract into the brain. Two subtypes of voltage-activated calcium play a major role in signal transmission: a low voltage-activated CaV3.2 channel and a high voltage-activated CaV2.2 channel. The CaV3.2 channel contributes mainly to the signal conductance along nociceptive neurons while the principal role of the CaV2.2 channel is in the synaptic transmission at the dorsal horn. Both channels contribute to the signal initiation at peripheral nerve endings. This review summarizes current knowledge about the expression and distribution of these channels in a nociceptive pathway, the regulation of their expression and gating during pain pathology, and their suitability as targets for pharmacological therapy.
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13
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Li R, Ou M, Yang S, Huang J, Chen J, Xiong D, Xiao L, Wu S. Change in Cav3.2 T-Type Calcium Channel Induced by Varicella-Zoster Virus Participates in the Maintenance of Herpetic Neuralgia. Front Neurol 2021; 12:741054. [PMID: 34917013 PMCID: PMC8671009 DOI: 10.3389/fneur.2021.741054] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/27/2021] [Indexed: 11/13/2022] Open
Abstract
Pain, as the most prevalent neurological complication of herpes zoster (HZ), may occur before or during the rash onset or even after the rash has recovered. Particularly, postherpetic neuralgia (PHN) is a refractory chronic condition, usually defined as pain persisting for 3 months or longer from the onset of HZ. Pain evoked by HZ impairs the normal physical and emotional functions of the patients, severely reducing their quality of life. However, how zoster-associated pain occurs and develops into PHN are elusive, making PHN difficult to predict. Uncovering the pathogenesis of zoster-associated pain (or HN) helps us to better understand the onset of PHN and supports developing more effective treatments. In this study, we successfully constructed a model for zoster-associated pain through varicella-zoster virus (VZV) infections of mouse footpads and pain behavior assessments. Next, we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO) to analyze PHN rodent dorsal root ganglion (DRG) gene microarray data and found that calcium signal disorder might be involved in the onset of PHN. By using reverse transcription real-time fluorescent quantitative PCR (RT-qPCR) and Western blotting, we confirmed that VZV infection could significantly upregulate the expression of T-type calcium channel Cav3.2 in DRG and spinal dorsal horn (SDH). Intrathecal administration of Cav3.2 blocker (2R/S)-6-prenylnaringenin (6-PNG) relieved mechanical and thermal hyperalgesia induced by VZV. Taken together, our data indicated that VZV might participate in the occurrence and development of HN by upregulating the expression of Cav3.2 in DRG and SDH. These findings will help to reveal the underlying mechanisms on long-lasting pain and PHN formation, providing a new insight that Cav3.2 can be the promising drug target for remitting PHN.
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Affiliation(s)
- Rongzhen Li
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Mingxi Ou
- Department of Chemistry, University of Science and Technology of China, Hefei, China
| | - Shaomin Yang
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Jiabin Huang
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | | | - Donglin Xiong
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Lizu Xiao
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Songbin Wu
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
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14
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Alles SRA, Smith PA. Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. FRONTIERS IN PAIN RESEARCH 2021; 2:750583. [PMID: 35295464 PMCID: PMC8915663 DOI: 10.3389/fpain.2021.750583] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/10/2021] [Indexed: 11/25/2022] Open
Abstract
The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.
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Affiliation(s)
- Sascha R A Alles
- Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Peter A Smith
- Department of Pharmacology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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15
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Hoffmann T, Kistner K, Joksimovic SLJ, Todorovic SM, Reeh PW, Sauer SK. Painful diabetic neuropathy leads to functional Ca V3.2 expression and spontaneous activity in skin nociceptors of mice. Exp Neurol 2021; 346:113838. [PMID: 34450183 PMCID: PMC8549116 DOI: 10.1016/j.expneurol.2021.113838] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/15/2021] [Accepted: 08/07/2021] [Indexed: 12/26/2022]
Abstract
Painful diabetic neuropathy occurs in approximately 20% of diabetic patients with underlying pathomechanisms not fully understood. We evaluated the contribution of the CaV3.2 isoform of T-type calcium channel to hyperglycemia-induced changes in cutaneous sensory C-fiber functions and neuropeptide release employing the streptozotocin (STZ) diabetes model in congenic mouse strains including global knockouts (KOs). Hyperglycemia established for 3-5 weeks in male C57BL/6J mice led to major reorganizations in peripheral C-fiber functions. Unbiased electrophysiological screening of mechanosensitive single-fibers in isolated hairy hindpaw skin revealed a relative loss of (polymodal) heat sensing in favor of cold sensing. In healthy CaV3.2 KO mice both heat and cold sensitivity among the C-fibers seemed underrepresented in favor of exclusive mechanosensitivity, low-threshold in particular, which deficit became significant in the diabetic KOs. Diabetes also led to a marked increase in the incidence of spontaneous discharge activity among the C-fibers of wildtype mice, which was reduced by the specific CaV3.2 blocker TTA-P2 and largely absent in the KOs. Evaluation restricted to the peptidergic class of nerve fibers - measuring KCl-stimulated CGRP release - revealed a marked reduction in the sciatic nerve by TTA-P2 in healthy but not diabetic wildtypes, the latter showing CGRP release that was as much reduced as in healthy and, to the same extent, in diabetic CaV3.2 KOs. These data suggest that diabetes abrogates all CaV3.2 functionality in the peripheral nerve axons. In striking contrast, diabetes markedly increased the KCl-stimulated CGRP release from isolated hairy skin of wildtypes but not KO mice, and TTA-P2 reversed this increase, strongly suggesting a de novo expression of CaV3.2 in peptidergic cutaneous nerve endings which may contribute to the enhanced spontaneous activity. De-glycosylation by neuraminidase showed clear desensitizing effects, both in regard to spontaneous activity and stimulated CGRP release, but included actions independent of CaV3.2. However, as diabetes-enhanced glycosylation is decisive for intra-axonal trafficking, it may account for the substantial reorganizations of the CaV3.2 distribution. The results may strengthen the validation of CaV3.2 channel as a therapeutic target of treating painful diabetic neuropathy.
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Affiliation(s)
- Tal Hoffmann
- Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany
| | - Katrin Kistner
- Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany
| | - Sonja L J Joksimovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Peter W Reeh
- Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany
| | - Susanne K Sauer
- Institute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
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16
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Regulation of Ca V3.2 channels by the receptor for activated C kinase 1 (Rack-1). Pflugers Arch 2021; 474:447-454. [PMID: 34623515 DOI: 10.1007/s00424-021-02631-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 01/27/2023]
Abstract
This study describes the interaction between CaV3.2 calcium channels and the receptor for activated C kinase 1 (Rack-1), a scaffold protein which has recently been implicated in neuropathic pain. The coexpression of CaV3.2 and Rack-1 in tsA-201 cells led to a reduction in the magnitude of whole-cell CaV3.2 currents and CaV3.2 channel expression at the plasma membrane. Co-immunoprecipitations from transfected cells show the formation of a molecular protein complex between Cav3.2 channels and Rack-1. We determined that the interaction of Rack-1 occurs at the intracellular II-III loop and the C-terminus of the channel. Finally, the coexpression of PKCβII abolished the effect of Rack-1 on current densities. Altogether, our findings show that Rack-1 regulates CaV3.2-mediated calcium entry in a PKC-dependent manner.
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17
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Targeting T-type/CaV3.2 channels for chronic pain. Transl Res 2021; 234:20-30. [PMID: 33422652 PMCID: PMC8217081 DOI: 10.1016/j.trsl.2021.01.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 01/09/2023]
Abstract
T-type calcium channels regulate neuronal excitability and are important contributors of pain processing. CaV3.2 channels are the major isoform expressed in nonpeptidergic and peptidergic nociceptive neurons and are emerging as promising targets for pain treatment. Numerous studies have shown that CaV3.2 expression and/or activity are significantly increased in spinal dorsal horn and in dorsal root ganglia neurons in different inflammatory and neuropathic pain models. Pharmacological campaigns to inhibit the functional expression of CaV3.2 for treatment of pain have focused on the development of direct channel blockers, but none have produced lead candidates. Targeting the proteins that regulate the trafficking or transcription, and the ones that modify the channels via post-translational modifications are alternative means to regulate expression and function of CaV3.2 channels and hence to develop new drugs to control pain. Here we synthesize data supporting a role for CaV3.2 in numerous pain modalities and then discuss emerging opportunities for the indirect targeting of CaV3.2 channels.
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18
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Affiliation(s)
- Norbert Weiss
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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19
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Ferron L, Koshti S, Zamponi GW. The life cycle of voltage-gated Ca 2+ channels in neurons: an update on the trafficking of neuronal calcium channels. Neuronal Signal 2021; 5:NS20200095. [PMID: 33664982 PMCID: PMC7905535 DOI: 10.1042/ns20200095] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/15/2021] [Indexed: 01/26/2023] Open
Abstract
Neuronal voltage-gated Ca2+ (CaV) channels play a critical role in cellular excitability, synaptic transmission, excitation-transcription coupling and activation of intracellular signaling pathways. CaV channels are multiprotein complexes and their functional expression in the plasma membrane involves finely tuned mechanisms, including forward trafficking from the endoplasmic reticulum (ER) to the plasma membrane, endocytosis and recycling. Whether genetic or acquired, alterations and defects in the trafficking of neuronal CaV channels can have severe physiological consequences. In this review, we address the current evidence concerning the regulatory mechanisms which underlie precise control of neuronal CaV channel trafficking and we discuss their potential as therapeutic targets.
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Affiliation(s)
- Laurent Ferron
- Department of Physiology and Pharmacology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Saloni Koshti
- Department of Physiology and Pharmacology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Gerald W. Zamponi
- Department of Physiology and Pharmacology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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20
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Abstract
Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.
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21
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Deshpande D, Agarwal N, Fleming T, Gaveriaux-Ruff C, Klose CSN, Tappe-Theodor A, Kuner R, Nawroth P. Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy. Nat Commun 2021; 12:426. [PMID: 33462216 PMCID: PMC7814083 DOI: 10.1038/s41467-020-20677-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
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Affiliation(s)
- Divija Deshpande
- grid.5253.10000 0001 0328 4908Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410 Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Institute of Pharmacology, Heidelberg University, INF 366, Heidelberg, 69120 Germany ,grid.6363.00000 0001 2218 4662Department of Microbiology, Infectious Diseases and Immunology, Charité -Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Nitin Agarwal
- grid.7700.00000 0001 2190 4373Institute of Pharmacology, Heidelberg University, INF 366, Heidelberg, 69120 Germany
| | - Thomas Fleming
- grid.5253.10000 0001 0328 4908Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410 Heidelberg, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Claire Gaveriaux-Ruff
- grid.420255.40000 0004 0638 2716Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics, Illkirch, France ,grid.420255.40000 0004 0638 2716Université de Strasbourg, Illkirch, France ,grid.4444.00000 0001 2112 9282Centre National de la Recherche Scientifique, UMR7104 Illkirch, France ,Institut National de la Santé et de la Recherche Médicale, U1258 Illkirch, France ,grid.418692.00000 0004 0610 0264Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France
| | - Christoph S. N. Klose
- grid.6363.00000 0001 2218 4662Department of Microbiology, Infectious Diseases and Immunology, Charité -Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Anke Tappe-Theodor
- grid.7700.00000 0001 2190 4373Institute of Pharmacology, Heidelberg University, INF 366, Heidelberg, 69120 Germany
| | - Rohini Kuner
- grid.7700.00000 0001 2190 4373Institute of Pharmacology, Heidelberg University, INF 366, Heidelberg, 69120 Germany
| | - Peter Nawroth
- grid.5253.10000 0001 0328 4908Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410 Heidelberg, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany ,Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Zentrum, 85764 Neuherberg, Germany
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22
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Joksimovic SL, Evans JG, McIntire WE, Orestes P, Barrett PQ, Jevtovic-Todorovic V, Todorovic SM. Glycosylation of Ca V3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes. Front Cell Neurosci 2020; 14:605312. [PMID: 33384586 PMCID: PMC7770106 DOI: 10.3389/fncel.2020.605312] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 11/18/2020] [Indexed: 01/19/2023] Open
Abstract
Our previous studies implicated glycosylation of the CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant CaV3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our in vitro study we used whole-cell recordings of current-voltage relationships to confirm that CaV3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced in vivo by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and CaV3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the CaV3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native CaV3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in CaV3.2 channels in vivo directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.
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Affiliation(s)
- Sonja Lj Joksimovic
- Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States
| | - J Grayson Evans
- Undergraduate School of Arts and Sciences, University of Virginia, Charlottesville, VA, United States
| | - William E McIntire
- Department of Molecular Physiology and Biological Physics, University of Virginia Health System, Charlottesville, VA, United States
| | - Peihan Orestes
- Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, United States
| | - Paula Q Barrett
- Department of Pharmacology, University of Virginia, Charlottesville, VA, United States
| | | | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States.,Neuroscience Graduate Program and Graduate Program in Pharmacology, University of Colorado Denver, Aurora, CO, United States
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23
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Ficelova V, Souza IA, Cmarko L, Gandini MA, Stringer RN, Zamponi GW, Weiss N. Functional identification of potential non-canonical N-glycosylation sites within Ca v3.2 T-type calcium channels. Mol Brain 2020; 13:149. [PMID: 33176830 PMCID: PMC7659234 DOI: 10.1186/s13041-020-00697-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/06/2020] [Indexed: 01/14/2023] Open
Abstract
Low-voltage-activated T-type calcium channels are important contributors to nervous system function. Post-translational modification of these channels has emerged as an important mechanism to control channel activity. Previous studies have documented the importance of asparagine (N)-linked glycosylation and identified several asparagine residues within the canonical consensus sequence N-X-S/T that is essential for the expression and function of Cav3.2 channels. Here, we explored the functional role of non-canonical N-glycosylation motifs in the conformation N-X-C based on site directed mutagenesis. Using a combination of electrophysiological recordings and surface biotinylation assays, we show that asparagines N345 and N1780 located in the motifs NVC and NPC, respectively, are essential for the expression of the human Cav3.2 channel in the plasma membrane. Therefore, these newly identified asparagine residues within non-canonical motifs add to those previously reported in canonical sites and suggest that N-glycosylation of Cav3.2 may also occur at non-canonical motifs to control expression of the channel in the plasma membrane. It is also the first study to report the functional importance of non-canonical N-glycosylation motifs in an ion channel.
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Affiliation(s)
- Vendula Ficelova
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.,Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Ivana A Souza
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Leos Cmarko
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.,Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Maria A Gandini
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Robin N Stringer
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.,Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Norbert Weiss
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. .,Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
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24
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Lory P, Nicole S, Monteil A. Neuronal Cav3 channelopathies: recent progress and perspectives. Pflugers Arch 2020; 472:831-844. [PMID: 32638069 PMCID: PMC7351805 DOI: 10.1007/s00424-020-02429-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/08/2020] [Accepted: 06/26/2020] [Indexed: 12/22/2022]
Abstract
T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knock-out mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.
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Affiliation(s)
- Philippe Lory
- Institut de Génomique Fonctionnelle, CNRS, INSERM, University Montpellier, 141, rue de la Cardonille, 34094, Montpellier, France. .,LabEx 'Ion Channel Science and Therapeutics' (ICST), Montpellier, France.
| | - Sophie Nicole
- Institut de Génomique Fonctionnelle, CNRS, INSERM, University Montpellier, 141, rue de la Cardonille, 34094, Montpellier, France.,LabEx 'Ion Channel Science and Therapeutics' (ICST), Montpellier, France
| | - Arnaud Monteil
- Institut de Génomique Fonctionnelle, CNRS, INSERM, University Montpellier, 141, rue de la Cardonille, 34094, Montpellier, France.,LabEx 'Ion Channel Science and Therapeutics' (ICST), Montpellier, France
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25
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Stringer RN, Lazniewska J, Weiss N. Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Ca v3.2 channels. Channels (Austin) 2020; 14:132-140. [PMID: 32233724 PMCID: PMC7153791 DOI: 10.1080/19336950.2020.1745406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation of the channel may contribute to the aberrant expression of the channel in diabetic conditions. In this study, we aimed to analyze the expression of glycan-processing genes in DRG neurons from a leptin-deficient genetic mouse model of diabetes (db/db). Transcriptomic analysis revealed that several glycan-processing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Cav3.2 revealed an unexpected loss-of-function of the channel. Collectively, our data indicate that diabetes is associated with an alteration of the glycosylation machinery in DRG neurons. However, individual action of these enzymes when tested on recombinant Cav3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions. Abbreviations: Galnt16: Polypeptide N-acetylgalactosaminyltransferase 16; B3gnt8: UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 8; B4galt1: Beta-1,4-galactosyltransferase 1; St6gal1: Beta-galactoside alpha-2,6-sialyltransferase 1; Neu3: Sialidase-3
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Affiliation(s)
- Robin N Stringer
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Joanna Lazniewska
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Norbert Weiss
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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Huang D, Shi S, Liang C, Zhang X, Du X, An H, Peers C, Zhang H, Gamper N. Delineating an extracellular redox-sensitive module in T-type Ca 2+ channels. J Biol Chem 2020; 295:6177-6186. [PMID: 32188693 PMCID: PMC7196644 DOI: 10.1074/jbc.ra120.012668] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/17/2020] [Indexed: 01/04/2023] Open
Abstract
T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.
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Affiliation(s)
- Dongyang Huang
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China; Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050000, China
| | - Sai Shi
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin 300401, China
| | - Ce Liang
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China
| | - Xiaoyu Zhang
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China
| | - Xiaona Du
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China
| | - Hailong An
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin 300401, China
| | - Chris Peers
- Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Hailin Zhang
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China.
| | - Nikita Gamper
- Department of Pharmacology, Hebei Medical University, Shijiazhuang 050000, China; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
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28
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Weiss N, Zamponi GW. Genetic T-type calcium channelopathies. J Med Genet 2020; 57:1-10. [PMID: 31217264 PMCID: PMC6929700 DOI: 10.1136/jmedgenet-2019-106163] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/02/2019] [Accepted: 05/18/2019] [Indexed: 12/13/2022]
Abstract
T-type channels are low-voltage-activated calcium channels that contribute to a variety of cellular and physiological functions, including neuronal excitability, hormone and neurotransmitter release as well as developmental aspects. Several human conditions including epilepsy, autism spectrum disorders, schizophrenia, motor neuron disorders and aldosteronism have been traced to variations in genes encoding T-type channels. In this short review, we present the genetics of T-type channels with an emphasis on structure-function relationships and associated channelopathies.
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Affiliation(s)
- Norbert Weiss
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Praha, Czech Republic
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Gandini MA, Souza IA, Raval D, Xu J, Pan YX, Zamponi GW. Differential regulation of Cav2.2 channel exon 37 variants by alternatively spliced μ-opioid receptors. Mol Brain 2019; 12:98. [PMID: 31775826 PMCID: PMC6880636 DOI: 10.1186/s13041-019-0524-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 11/14/2019] [Indexed: 12/15/2022] Open
Abstract
We have examined the regulation of mutually exclusive Cav2.2 exon 37a and b variants by the mouse μ-opioid receptor (mMOR) C-terminal splice variants 1, 1C and 1O in tsA-201 cells. Electrophysiological analyses revealed that both channel isoforms exhibit DAMGO-induced voltage-dependent (Gβγ-mediated) inhibition and its recovery by voltage pre-pulses, as well as a voltage-independent component. However, the two channel isoforms differ in their relative extent of voltage-dependent and independent inhibition, with Cav2.2-37b showing significantly more voltage-dependent inhibition upon activation of the three mMOR receptors studied. In addition, coexpression of either mMOR1 or mMOR1C results in an agonist-independent reduction in the peak current density of Cav2.2-37a channels, whereas the peak current density of Cav2.2-37b does not appear to be affected. Interestingly, this decrease is not due to an effect on channel expression at the plasma membrane, as demonstrated by biotinylation experiments. We further examined the mechanism underlying the agonist-independent modulation of Cav2.2-37a by mMOR1C. Incubation of cells with pertussis toxin did not affect the mMOR1C mediated inhibition of Cav2.2-37a currents, indicating a lack of involvement of Gi/o signaling. However, when a Src tyrosine kinase inhibitor was applied, the effect of mMOR1C was lost. Moreover, when we recorded currents using a Cav2.2-37a mutant in which tyrosine 1747 was replaced with phenylalanine (Y1747F), the agonist independent effects of mMOR1C were abolished. Altogether our findings show that Cav2.2-37a and Cav2.2-37b isoforms are subject to differential regulation by C-terminal splice variants of mMORs, and that constitutive mMOR1C activity and downstream tyrosine kinase activity exert a selective inhibition of the Cav2.2-37a splice variant, an N-type channel isoform that is highly enriched in nociceptors. Our study provides new insights into the roles of the MOR full-length C-terminal variants in modulating Cav2.2 channel isoform activities.
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Affiliation(s)
- Maria A Gandini
- Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Ivana A Souza
- Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dvij Raval
- Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jin Xu
- Department of Neurology and the Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Ying-Xian Pan
- Department of Neurology and the Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Sekiguchi F, Kawabata A. [Role of Ca v3.2 T-type Ca 2+ channels in prostate cancer cells]. Nihon Yakurigaku Zasshi 2019; 154:97-102. [PMID: 31527367 DOI: 10.1254/fpj.154.97] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Among voltage-gated Ca2+ channels, T-type Ca2+ channels, which are activated by low voltages, regulate neuronal excitability, spontaneous neurotransmitter release, hormone secretion, etc. and also participate in proliferation of distinct cancer cells. Among three isoforms of T-type Ca2+ channels, Cav3.2 is detectable in 100% of biopsy samples from prostate cancer patients. In general, prostate cancer cells are highly sensitive to androgen deprivation therapy, but often acquire hormone-therapy resistance. The androgen deprivation may trigger neuroendocrine (NE)-like differentiation of some prostate cancer cells. We have analyzed the expression and function of Cav3.2 in human prostate cancer LNCaP cells during NE-like differentiation. NE-like LNCaP cells overexpress Cav3.2 through the CREB/Egr-1 pathway and also cystathionine-γ-lyase (CSE), which generates H2S that enhances the channel activity of Cav3.2. H2S generated by upregulated CSE appears to enhance the activity of upregulated Cav3.2 after the differentiation. The enhanced Cav3.2 activity in NE-like cells may contribute to increased secretion of mitogenic factors essential for androgen-independent proliferation of surrounding prostate cancer cells. It is known that increased extracellular glucose levels enhance Cav3.2 activity through asparagine (N)-linked glycosylation of Cav3.2, which might contribute to diabetic neuropathy. We then found that high glucose accelerates the enhanced channel function and overexpression of Cav3.2 in NE-like LNCaP cells, which might be associated with clinical evidence for diabetes-related poor prognosis of prostate cancer and development of hormone therapy resistance. Thus, Cav3.2 is considered to play a role in the pathophysiology of prostate cancer, and may serve as a therapeutic target.
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Affiliation(s)
- Fumiko Sekiguchi
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University
| | - Atsufumi Kawabata
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University
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31
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Jurkovicova-Tarabova B, Mackova K, Moravcikova L, Karmazinova M, Lacinova L. Role of individual S4 segments in gating of Ca v3.1 T-type calcium channel by voltage. Channels (Austin) 2019; 12:378-387. [PMID: 30403912 PMCID: PMC6287678 DOI: 10.1080/19336950.2018.1543520] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Contributions of voltage sensing S4 segments in domains I – IV of CaV3.1 channel to channel activation were analyzed. Neutralization of the uppermost charge in individual S4 segments by exchange of arginine for cysteine was employed. Mutant channels with single exchange in domains I – IV, in two adjacent domains, and in all four domains were constructed and expressed in HEK 293 cells. Changes in maximal gating charge Qmax and the relation between Qmax and maximal conductance Gmax were evaluated. Qmax was the most affected by single mutation in domain I and by double mutations in domains I + II and I + IV. The ratio Gmax/Qmax proportional to opening probability of the channel was significantly decreased by the mutation in domain III and increased by mutations in domains I and II. In channels containing double mutations Gmax/Qmax ratio increased significantly when the mutation in domain I was included. Mutations in domains II and III zeroed each other. Mutation in domain IV prevented the decrease caused by the mutation in domain III. Neither ion current nor gating current was observed when channels with quadruple mutations were expressed. Immunocytochemistry analysis did not reveal the presence of channel protein in the cell membrane. Likely, quadruple mutation results in a structural change that affects the channel’s trafficking mechanism. Altogether, S4 segments in domains I-IV of the CaV3.1 channel unequally contribute to channel gating by voltage. We suggest the most important role of the voltage sensor in the domain I and lesser roles of voltage sensors in domains II and III.
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Affiliation(s)
- Bohumila Jurkovicova-Tarabova
- a Center of Biosciences, Institute of Molecular Physiology and Genetics , Academy of Sciences , Bratislava , Slovakia
| | - Katarina Mackova
- a Center of Biosciences, Institute of Molecular Physiology and Genetics , Academy of Sciences , Bratislava , Slovakia
| | - Lucia Moravcikova
- a Center of Biosciences, Institute of Molecular Physiology and Genetics , Academy of Sciences , Bratislava , Slovakia
| | - Maria Karmazinova
- a Center of Biosciences, Institute of Molecular Physiology and Genetics , Academy of Sciences , Bratislava , Slovakia
| | - Lubica Lacinova
- a Center of Biosciences, Institute of Molecular Physiology and Genetics , Academy of Sciences , Bratislava , Slovakia.,b Faculty of Natural Sciences , University of Ss. Cyril and Methodius , Trnava , Slovakia
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32
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A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy. Pain 2019; 160:2798-2810. [DOI: 10.1097/j.pain.0000000000001669] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primers 2019; 5:42. [PMID: 31197183 PMCID: PMC7096070 DOI: 10.1038/s41572-019-0097-9] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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Affiliation(s)
- Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA.,
| | | | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes (MEND), University of Michigan, Ann Arbor, MI, USA
| | - Douglas W. Zochodne
- Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas E. Wright
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - David L. Bennett
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Vera Bril
- Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada.,Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - James W. Russell
- Department of Neurology, University of Maryland and VA Maryland Health Care System, Baltimore, MD, USA
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Liu Y, Wang P, Ma F, Zheng M, Liu G, Kume S, Kurokawa T, Ono K. Asparagine-linked glycosylation modifies voltage-dependent gating properties of Ca V3.1-T-type Ca 2+ channel. J Physiol Sci 2019; 69:335-343. [PMID: 30600443 PMCID: PMC10717069 DOI: 10.1007/s12576-018-0650-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/05/2018] [Indexed: 01/11/2023]
Abstract
T-type channels are low-voltage-activated channels that play a role in the cardiovascular system particularly for pacemaker activity. Glycosylation is one of the most prevalent post-translational modifications in protein. Among various glycosylation types, the most common one is asparagine-linked (N-linked) glycosylation. The aim of this study was to elucidate the roles of N-linked glycosylation for the gating properties of the CaV3.1-T-type Ca2+ channel. N-linked glycosylation synthesis inhibitor tunicamycin causes a reduction of CaV3.1-T-type Ca2+ channel current (CaV3.1-ICa.T) when applied for 12 h or longer. Tunicamycin (24 h) significantly shifted the activation curve to the depolarization potentials, whereas the steady-state inactivation curve was unaffected. Use-dependent inactivation of CaV3.1-ICa.T was accelerated, and recovery from inactivation was prolonged by tunicamycin (24 h). CaV3.1-ICa.T was insensitive to a glycosidase PNGase F when the channels were expressed on the plasma membrane. These findings suggest that N-glycosylation contributes not only to the cell surface expression of the CaV3.1-T-type Ca2+ channel but to the regulation of the gating properties of the channel when the channel proteins were processed during the folding and trafficking steps in the cell.
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Affiliation(s)
- Yangong Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Pu Wang
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Fangfang Ma
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Mingqi Zheng
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
| | - Shinichiro Kume
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Tatsuki Kurokawa
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Katsushige Ono
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan.
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T-type calcium channels: From molecule to therapeutic opportunities. Int J Biochem Cell Biol 2019; 108:34-39. [DOI: 10.1016/j.biocel.2019.01.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/11/2019] [Indexed: 12/27/2022]
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Zhang Y, Jiang D, Li H, Sun Y, Jiang X, Gong S, Qian Z, Tao J. Melanocortin type 4 receptor-mediated inhibition of A-type K + current enhances sensory neuronal excitability and mechanical pain sensitivity in rats. J Biol Chem 2019; 294:5496-5507. [PMID: 30745360 DOI: 10.1074/jbc.ra118.006894] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/07/2019] [Indexed: 12/28/2022] Open
Abstract
α-Melanocyte-stimulating hormone (α-MSH) has been shown to be involved in nociception, but the underlying molecular mechanisms remain largely unknown. In this study, we report that α-MSH suppresses the transient outward A-type K+ current (I A) in trigeminal ganglion (TG) neurons and thereby modulates neuronal excitability and peripheral pain sensitivity in rats. Exposing small-diameter TG neurons to α-MSH concentration-dependently decreased I A This α-MSH-induced I A decrease was dependent on the melanocortin type 4 receptor (MC4R) and associated with a hyperpolarizing shift in the voltage dependence of A-type K+ channel inactivation. Chemical inhibition of phosphatidylinositol 3-kinase (PI3K) with wortmannin or of class I PI3Ks with the selective inhibitor CH5132799 prevented the MC4R-mediated I A response. Blocking Gi/o-protein signaling with pertussis toxin or by dialysis of TG neurons with the Gβγ-blocking synthetic peptide QEHA abolished the α-MSH-mediated decrease in I A Further, α-MSH increased the expression levels of phospho-p38 mitogen-activated protein kinase, and pharmacological or genetic inhibition of p38α abrogated the α-MSH-induced I A response. Additionally, α-MSH significantly increased the action potential firing rate of TG neurons and increased the sensitivity of rats to mechanical stimuli applied to the buccal pad area, and both effects were abrogated by I A blockade. Taken together, our findings suggest that α-MSH suppresses I A by activating MC4R, which is coupled sequentially to the Gβγ complex of the Gi/o-protein and downstream class I PI3K-dependent p38α signaling, thereby increasing TG neuronal excitability and mechanical pain sensitivity in rats.
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Affiliation(s)
- Yuan Zhang
- From the Department of Geriatrics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.,the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China
| | - Dongsheng Jiang
- the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China.,the Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich 81377, Germany, and
| | - Hua Li
- the National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai 201203, China
| | - Yufang Sun
- the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China
| | - Xinghong Jiang
- the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China
| | - Shan Gong
- the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China
| | - Zhiyuan Qian
- From the Department of Geriatrics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China,
| | - Jin Tao
- the Department of Physiology and Neurobiology and Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, China, .,the Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215123, China
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38
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Feng XJ, Ma LX, Jiao C, Kuang HX, Zeng F, Zhou XY, Cheng XE, Zhu MY, Zhang DY, Jiang CY, Liu T. Nerve injury elevates functional Cav3.2 channels in superficial spinal dorsal horn. Mol Pain 2019; 15:1744806919836569. [PMID: 30803310 PMCID: PMC6458665 DOI: 10.1177/1744806919836569] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/02/2019] [Accepted: 02/12/2019] [Indexed: 01/23/2023] Open
Abstract
Cav3 channels play an important role in modulating chronic pain. However, less is known about the functional changes of Cav3 channels in superficial spinal dorsal horn in neuropathic pain states. Here, we examined the effect of partial sciatic nerve ligation (PSNL) on either expression or electrophysiological properties of Cav3 channels in superficial spinal dorsal horn. Our in vivo studies showed that the blockers of Cav3 channels robustly alleviated PSNL-induced mechanical allodynia and thermal hyperalgesia, which lasted at least 14 days following PSNL. Meanwhile, PSNL triggered an increase in both mRNA and protein levels of Cav3.2 but not Cav3.1 or Cav3.3 in rats. However, in Cav3.2 knockout mice, PSNL predominantly attenuated mechanical allodynia but not thermal hyperalgesia. In addition, the results of whole-cell patch-clamp recordings showed that both the overall proportion of Cav3 current-expressing neurons and the Cav3 current density in individual neurons were elevated in spinal lamina II neurons from PSNL rats, which could not be recapitulated in Cav3.2 knockout mice. Altogether, our findings reveal that the elevated functional Cav3.2 channels in superficial spinal dorsal horn may contribute to the mechanical allodynia in PSNL-induced neuropathic pain model.
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Affiliation(s)
- Xiao-Jin Feng
- Center for Experimental Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Long-Xian Ma
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Cui Jiao
- Department of Pediatrics, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hai-Xia Kuang
- Department of Pediatrics, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fei Zeng
- Department of Pain Clinic, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xue-Ying Zhou
- Department of Pediatrics, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao-E Cheng
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Meng-Ye Zhu
- Department of Pain Clinic, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Da-Ying Zhang
- Department of Pain Clinic, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chang-Yu Jiang
- Jisheng Han Academician Workstation for Pain Medicine, Nanshan Hospital, Shenzhen, China
| | - Tao Liu
- Center for Experimental Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Pediatrics, the First Affiliated Hospital of Nanchang University, Nanchang, China
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Wang D, Ragnarsson L, Lewis RJ. T-type Calcium Channels in Health and Disease. Curr Med Chem 2018; 27:3098-3122. [PMID: 30277145 DOI: 10.2174/0929867325666181001112821] [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] [Received: 07/06/2018] [Revised: 08/28/2018] [Accepted: 08/30/2018] [Indexed: 12/12/2022]
Abstract
Low Voltage-Activated (LVA) T-type calcium channels are characterized by transient current and Low Threshold Spikes (LTS) that trigger neuronal firing and oscillatory behavior. Combined with their preferential localization in dendrites and their specific "window current", T-type calcium channels are considered to be key players in signal amplification and synaptic integration. Assisted by the emerging pharmacological tools, the structural determinants of channel gating and kinetics, as well as novel physiological and pathological functions of T-type calcium channels, are being uncovered. In this review, we provide an overview of structural determinants in T-type calcium channels, their involvement in disorders and diseases, the development of novel channel modulators, as well as Structure-Activity Relationship (SAR) studies that lead to rational drug design.
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Affiliation(s)
- Dan Wang
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane Qld 4072, Australia
| | - Lotten Ragnarsson
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane Qld 4072, Australia
| | - Richard J Lewis
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, the University of Queensland, Brisbane Qld 4072, Australia
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40
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Joksimovic SL, Joksimovic SM, Tesic V, García-Caballero A, Feseha S, Zamponi GW, Jevtovic-Todorovic V, Todorovic SM. Selective inhibition of Ca V3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain. Sci Signal 2018; 11:eaao4425. [PMID: 30154101 PMCID: PMC6193449 DOI: 10.1126/scisignal.aao4425] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized or hyperexcitable in response to surgically induced peripheral tissue injury. We investigated the potential role and molecular mechanisms of nociceptive ion channel dysregulation in acute pain conditions such as those resulting from skin and soft tissue incision. We used selective pharmacology, electrophysiology, and mouse genetics to link increased current densities arising from the CaV3.2 isoform of T-type calcium channels (T-channels) to nociceptive sensitization using a clinically relevant rodent model of skin and deep tissue incision. Furthermore, knockdown of the CaV3.2-targeting deubiquitinating enzyme USP5 or disruption of USP5 binding to CaV3.2 channels in peripheral nociceptors resulted in a robust antihyperalgesic effect in vivo and substantial T-current reduction in vitro. Our study provides mechanistic insight into the role of plasticity in CaV3.2 channel activity after surgical incision and identifies potential targets for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.
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Affiliation(s)
- Sonja L Joksimovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
- Pharmacology Graduate Program, School of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
| | - Srdjan M Joksimovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Vesna Tesic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Agustin García-Caballero
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1 Canada
| | - Simon Feseha
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1 Canada
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
- Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
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41
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Vastani N, Guenther F, Gentry C, Austin AL, King AJ, Bevan S, Andersson DA. Impaired Nociception in the Diabetic Ins2+/Akita Mouse. Diabetes 2018; 67:1650-1662. [PMID: 29875100 DOI: 10.2337/db17-1306] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 05/18/2018] [Indexed: 11/13/2022]
Abstract
The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2+/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2+/Akita mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in Ins2+/Akita dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplantation also restored Ins2+/Akita intraepidermal nerve fiber density to the same level as wild-type mice, indicating that restored insulin production can reverse both sensory and anatomical abnormalities of diabetic neuropathy in mice. The reduced rate of action potential discharge in nociceptive fibers and the impaired heat responsiveness of Ins2+/Akita DRG neurons suggest that ionic sensory transduction and transmission mechanisms are modified by diabetes.
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MESH Headings
- Action Potentials
- Amino Acid Substitution
- Animals
- Behavior, Animal
- Cells, Cultured
- Diabetes Mellitus/blood
- Diabetes Mellitus/surgery
- Diabetic Neuropathies/metabolism
- Diabetic Neuropathies/pathology
- Diabetic Neuropathies/physiopathology
- Diabetic Neuropathies/prevention & control
- Epidermis/innervation
- Epidermis/metabolism
- Epidermis/pathology
- Epidermis/physiopathology
- Ganglia, Spinal/metabolism
- Ganglia, Spinal/pathology
- Ganglia, Spinal/physiopathology
- Heterozygote
- Insulin/genetics
- Insulin/metabolism
- Islets of Langerhans Transplantation
- Kidney
- Male
- Mechanoreceptors/metabolism
- Mechanoreceptors/pathology
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Nerve Fibers, Unmyelinated/metabolism
- Nerve Fibers, Unmyelinated/pathology
- Pain Measurement
- Somatosensory Disorders/complications
- Somatosensory Disorders/metabolism
- Somatosensory Disorders/physiopathology
- Somatosensory Disorders/prevention & control
- Thermoreceptors/metabolism
- Thermoreceptors/pathology
- Thermoreceptors/physiopathology
- Transplantation, Heterotopic
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Affiliation(s)
- Nisha Vastani
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K
| | - Franziska Guenther
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K
- Institut für Physiologie und Pathophysiologie, Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Clive Gentry
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K
| | - Amazon L Austin
- Diabetes & Nutritional Sciences Division, King's College London, London, U.K
| | - Aileen J King
- Diabetes & Nutritional Sciences Division, King's College London, London, U.K
| | - Stuart Bevan
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K
| | - David A Andersson
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K.
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Sekiguchi F, Fujita T, Deguchi T, Yamaoka S, Tomochika K, Tsubota M, Ono S, Horaguchi Y, Ichii M, Ichikawa M, Ueno Y, Koike N, Tanino T, Nguyen HD, Okada T, Nishikawa H, Yoshida S, Ohkubo T, Toyooka N, Murata K, Matsuda H, Kawabata A. Blockade of T-type calcium channels by 6-prenylnaringenin, a hop component, alleviates neuropathic and visceral pain in mice. Neuropharmacology 2018; 138:232-244. [PMID: 29913186 DOI: 10.1016/j.neuropharm.2018.06.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/30/2018] [Accepted: 06/14/2018] [Indexed: 10/14/2022]
Abstract
Since Cav3.2 T-type Ca2+ channels (T-channels) expressed in the primary afferents and CNS contribute to intractable pain, we explored T-channel-blocking components in distinct herbal extracts using a whole-cell patch-clamp technique in HEK293 cells stably expressing Cav3.2 or Cav3.1, and purified and identified sophoraflavanone G (SG) as an active compound from SOPHORAE RADIX (SR). Interestingly, hop-derived SG analogues, (2S)-6-prenylnaringenin (6-PNG) and (2S)-8-PNG, but not naringenin, also blocked T-channels; IC50 (μM) of SG, (2S)-6-PNG and (2S)-8-PNG was 0.68-0.75 for Cav3.2 and 0.99-1.41 for Cav3.1. (2S)-6-PNG and (2S)-8-PNG, but not SG, exhibited reversible inhibition. The racemic (2R/S)-6-PNG as well as (2S)-6-PNG potently blocked Cav3.2, but exhibited minor effect on high-voltage-activated Ca2+ channels and voltage-gated Na+ channels in differentiated NG108-15 cells. In mice, the mechanical allodynia following intraplantar (i.pl.) administration of an H2S donor was abolished by oral or i.p. SR extract and by i.pl. SG, (2S)-6-PNG or (2S)-8-PNG, but not naringenin. Intraperitoneal (2R/S)-6-PNG strongly suppressed visceral pain and spinal ERK phosphorylation following intracolonic administration of an H2S donor in mice. (2R/S)-6-PNG, administered i.pl. or i.p., suppressed the neuropathic allodynia induced by partial sciatic nerve ligation or oxaliplatin, an anti-cancer agent, in mice. (2R/S)-6-PNG had little or no effect on open-field behavior, motor performance or cardiovascular function in mice, and on the contractility of isolated rat aorta. (2R/S)-6-PNG, but not SG, was detectable in the brain after their i.p. administration in mice. Our data suggest that 6-PNG, a hop component, blocks T-channels, and alleviates neuropathic and visceral pain with little side effects.
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Affiliation(s)
- Fumiko Sekiguchi
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Tomoyo Fujita
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Takahiro Deguchi
- Division of Natural Drug Resources, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Sakura Yamaoka
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Ken Tomochika
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Maho Tsubota
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Sumire Ono
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Yamato Horaguchi
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Maki Ichii
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Mio Ichikawa
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Yumiko Ueno
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Nene Koike
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Tadatoshi Tanino
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan
| | - Huy Du Nguyen
- Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-8555, Japan
| | - Takuya Okada
- Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-8555, Japan
| | - Hiroyuki Nishikawa
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Shigeru Yoshida
- Department of Life Science, Faculty of Science and Engineering, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Tsuyako Ohkubo
- Division of Basic Medical Sciences and Fundamental Nursing, Faculty of Nursing, Fukuoka Nursing College, Fukuoka, 814-0193, Japan
| | - Naoki Toyooka
- Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan
| | - Kazuya Murata
- Division of Natural Drug Resources, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Hideaki Matsuda
- Division of Natural Drug Resources, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan
| | - Atsufumi Kawabata
- Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, 577-8502, Japan.
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Zhao Q, Jia TZ, Cao QC, Tian F, Ying WT. A Crude 1-DNJ Extract from Home Made Bombyx Batryticatus Inhibits Diabetic Cardiomyopathy-Associated Fibrosis in db/db Mice and Reduces Protein N-Glycosylation Levels. Int J Mol Sci 2018; 19:ijms19061699. [PMID: 29880742 PMCID: PMC6032278 DOI: 10.3390/ijms19061699] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/26/2018] [Accepted: 05/29/2018] [Indexed: 01/01/2023] Open
Abstract
The traditional Chinese drug Bombyx Batryticatus (BB), which is also named the white stiff silkworm, has been widely used in Chinese clinics for thousands of years. It is famous for its antispasmodic and blood circulation-promoting effects. Cardiomyocyte hypertrophy, interstitial cell hyperplasia, and myocardial fibrosis are closely related to the N-glycosylation of key proteins. To examine the alterations of N-glycosylation that occur in diabetic myocardium during the early stage of the disease, and to clarify the therapeutic effect of 1-Deoxynojirimycin (1-DNJ) extracted from BB, we used the db/db (diabetic) mouse model and an approach based on hydrophilic chromatography solid-phase extraction integrated with an liquid Chromatograph Mass Spectrometer (LC-MS) identification strategy to perform a site-specific N-glycosylation analysis of left ventricular cardiomyocyte proteins. Advanced glycation end products (AGEs), hydroxyproline, connective tissue growth factor (CTGF), and other serum biochemical indicators were measured with enzyme-linked immunosorbent assays (ELISA). In addition, the α-1,6-fucosylation of N-glycans was profiled with lens culinaris agglutinin (LCA) lectin blots and fluorescein isothiocyanate (FITC)-labelled lectin affinity histochemistry. The results indicated that 1-DNJ administration obviously downregulated myocardium protein N-glycosylation in db/db mice. The expression levels of serum indicators and fibrosis-related cytokines were reduced significantly by 1-DNJ in a dose-dependent manner. The glycan α-1,6-fucosylation level of the db/db mouse myocardium was elevated, and the intervention effect of 1-DNJ administration on N-glycan α-1,6-fucosylation was significant. To verify this result, the well-known transforming growth factor-β (TGF-β)/Smad2/3 pathway was selected, and core α-1,6-fucosylated TGF-β receptor II (TGFR-βII) was analysed semi-quantitatively with western blotting. The result supported the conclusions obtained from LCA lectin affinity histochemistry and lectin blot analysis. The expression level of α-1,6-fucosyltransferase (FUT8) mRNA was also detected, and the results showed that 1-DNJ administration did not cause obvious inhibitory effects on FUT8 expression. Therefore, the mechanism of 1-DNJ for relieving diabetic cardiomyopathy (DCM)-associated fibrosis can be concluded as the inhibition of N-acetylglucosamine (N-GlcNAc) formation and the reduction of substrate concentration.
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Affiliation(s)
- Qing Zhao
- The Key Laboratory of Chinese Materia Medica Processing Principle Analysis of the State Administration of Traditional Chinese Medicine, Pharmaceutical College of Liaoning Traditional Chinese Medicine University, Chinese Materia Medica Processing Engineering Technology Research Center of Liaoning Province, Dalian 110060, China.
- Chinese Materia Medica Department, Traditional Chinese Medicine College of Hebei University, Baoding 071000, China.
- Beijing Institute of Lifeomics, Beijing Proteome Research Center, Beijing 102206, China.
| | - Tian Zhu Jia
- The Key Laboratory of Chinese Materia Medica Processing Principle Analysis of the State Administration of Traditional Chinese Medicine, Pharmaceutical College of Liaoning Traditional Chinese Medicine University, Chinese Materia Medica Processing Engineering Technology Research Center of Liaoning Province, Dalian 110060, China.
| | - Qi Chen Cao
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
| | - Fang Tian
- Beijing Institute of Lifeomics, Beijing Proteome Research Center, Beijing 102206, China.
| | - Wan Tao Ying
- Beijing Institute of Lifeomics, Beijing Proteome Research Center, Beijing 102206, China.
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Snutch TP, Zamponi GW. Recent advances in the development of T-type calcium channel blockers for pain intervention. Br J Pharmacol 2018; 175:2375-2383. [PMID: 28608534 PMCID: PMC5980537 DOI: 10.1111/bph.13906] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/19/2017] [Accepted: 06/05/2017] [Indexed: 01/15/2023] Open
Abstract
Cav 3.2 T-type calcium channels are important regulators of pain signals in the afferent pain pathway, and their activities are dysregulated during various chronic pain states. Therefore, it is reasonable to predict that inhibiting T-type calcium channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief. This is supported by early pharmacological studies with T-type channel blockers, such as ethosuximide, and by analgesic effects of siRNA depletion of Cav 3.2 channels. In the past 5 years, considerable effort has been applied towards identifying novel classes of T-type calcium channel blockers. Here, we review recent developments in the discovery of novel classes of T-type calcium channel blockers, and their analgesic effects in animal models of pain and in clinical trials. LINKED ARTICLES This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
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Affiliation(s)
- Terrance P Snutch
- Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain HealthUniversity of British ColumbiaVancouverBCCanada
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of MedicineUniversity of CalgaryCalgaryABCanada
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45
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Im SH, Patel AA, Cox DN, Galko MJ. Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization. Dis Model Mech 2018; 11:dmm034231. [PMID: 29752280 PMCID: PMC5992604 DOI: 10.1242/dmm.034231] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 03/25/2018] [Indexed: 12/12/2022] Open
Abstract
Diabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi -expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity.
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Affiliation(s)
- Seol Hee Im
- Department of Genetics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Atit A Patel
- Neuroscience Institute, Georgia State University, P.O. Box 5030, Atlanta, GA 30303, USA
| | - Daniel N Cox
- Neuroscience Institute, Georgia State University, P.O. Box 5030, Atlanta, GA 30303, USA
| | - Michael J Galko
- Department of Genetics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
- Genetics and Epigenetics Graduate Program, University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Avenue, Houston, TX 77030, USA
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Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy. Int J Mol Sci 2018; 19:ijms19020619. [PMID: 29470411 PMCID: PMC5855841 DOI: 10.3390/ijms19020619] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/15/2018] [Accepted: 02/18/2018] [Indexed: 02/01/2023] Open
Abstract
Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α₂δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.
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47
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Lacinová Ľ. Regulation of the Ca V3.2 calcium channels in health and disease Regulácia Ca V3.2 vápnikových kanálov v zdraví a chorobe. EUROPEAN PHARMACEUTICAL JOURNAL 2017. [DOI: 10.1515/afpuc-2017-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Family of T-type or low-voltage activated calcium channels consists of three members: CaV3.1, CaV3.2, and CaV3.3. CaV3.2 channel has almost identical biophysical properties as the CaV3.1 channel, but is distinguished by a specific tissue expression profile and a prominent role in several pathologies, including neuropathic pain, epilepsy, and dysregulation of cardiac rhythm. Further, it may be involved in phenotype of autism spectrum disorders, and amyotrophic lateral sclerosis. It represents a promising target for future pharmacotherapies.
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Affiliation(s)
- Ľ. Lacinová
- Slovenská akadémia vied, Biomedicínske centrum SAV, Bratislava , Slovakia
- Univerzita sv. Cyrila a Metoda v Trnave, Fakulta prírodných vied, Trnava , Slovakia
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48
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Mustafá ER, López Soto EJ, Martínez Damonte V, Rodríguez SS, Lipscombe D, Raingo J. Constitutive activity of the Ghrelin receptor reduces surface expression of voltage-gated Ca 2+ channels in a Ca Vβ-dependent manner. J Cell Sci 2017; 130:3907-3917. [PMID: 29038230 DOI: 10.1242/jcs.207886] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 10/04/2017] [Indexed: 12/15/2022] Open
Abstract
Voltage-gated Ca2+ (CaV) channels couple membrane depolarization to Ca2+ influx, triggering a range of Ca2+-dependent cellular processes. CaV channels are, therefore, crucial in shaping neuronal activity and function, depending on their individual temporal and spatial properties. Furthermore, many neurotransmitters and drugs that act through G protein coupled receptors (GPCRs), modulate neuronal activity by altering the expression, trafficking, or function of CaV channels. GPCR-dependent mechanisms that downregulate CaV channel expression levels are observed in many neurons but are, by comparison, less studied. Here we show that the growth hormone secretagogue receptor type 1a (GHSR), a GPCR, can inhibit the forwarding trafficking of several CaV subtypes, even in the absence of agonist. This constitutive form of GPCR inhibition of CaV channels depends on the presence of a CaVβ subunit. CaVβ subunits displace CaVα1 subunits from the endoplasmic reticulum. The actions of GHSR on CaV channels trafficking suggest a role for this signaling pathway in brain areas that control food intake, reward, and learning and memory.
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Affiliation(s)
- Emilio R Mustafá
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE), Universidad Nacional de La Plata - Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comisión de Investigaciones de la Provincia de buenos Aires (CIC) Calle 526 1499-1579, B1906APM Tolosa, Buenos Aires, Argentina
| | - Eduardo J López Soto
- Department of Neuroscience, Brown University; Sidney E. Frank Hall for Life Sciences, 185 Meeting Street, Providence, Rhode Island 02912, USA
| | - Valentina Martínez Damonte
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE), Universidad Nacional de La Plata - Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comisión de Investigaciones de la Provincia de buenos Aires (CIC) Calle 526 1499-1579, B1906APM Tolosa, Buenos Aires, Argentina
| | - Silvia S Rodríguez
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE), Universidad Nacional de La Plata - Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comisión de Investigaciones de la Provincia de buenos Aires (CIC) Calle 526 1499-1579, B1906APM Tolosa, Buenos Aires, Argentina
| | - Diane Lipscombe
- Department of Neuroscience, Brown University; Sidney E. Frank Hall for Life Sciences, 185 Meeting Street, Providence, Rhode Island 02912, USA
| | - Jesica Raingo
- Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE), Universidad Nacional de La Plata - Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comisión de Investigaciones de la Provincia de buenos Aires (CIC) Calle 526 1499-1579, B1906APM Tolosa, Buenos Aires, Argentina
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Yan YY, Li CY, Zhou L, Ao LY, Fang WR, Li YM. Research progress of mechanisms and drug therapy for neuropathic pain. Life Sci 2017; 190:68-77. [PMID: 28964813 DOI: 10.1016/j.lfs.2017.09.033] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 09/09/2017] [Accepted: 09/25/2017] [Indexed: 12/13/2022]
Abstract
Neuropathic pain is maladaptive pain caused by injury or dysfunction in peripheral and central nervous system, and remains a worldwide thorny problem leading to decreases in physical and mental quality of people's life. Currently, drug therapy is the main treatment regimen for resolving pain, while effective drugs are still unmet in medical need, and commonly used drugs such as anticonvulsants and antidepressants often make patients experience adverse drug reactions like dizziness, somnolence, severe headache, and high blood pressure. Thus, in this review we overview the anatomical physiology, underlying mechanisms of neuropathic pain to provide a better understanding in the initiation, development, maintenance, and modulation of this pervasive disease, and inspire research in the unclear mechanisms as well as potential targets. Furthermore, we summarized the existing drug therapies and new compounds that have shown antalgic effects in laboratory studies to be helpful for rational regimens in clinical treatment and promotion in novel drug discovery.
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Affiliation(s)
- Yun-Yi Yan
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Cheng-Yuan Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Lin Zhou
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Lu-Yao Ao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wei-Rong Fang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yun-Man Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
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50
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Feldman EL, Nave KA, Jensen TS, Bennett DLH. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 2017; 93:1296-1313. [PMID: 28334605 PMCID: PMC5400015 DOI: 10.1016/j.neuron.2017.02.005] [Citation(s) in RCA: 604] [Impact Index Per Article: 75.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 02/02/2017] [Accepted: 02/02/2017] [Indexed: 12/13/2022]
Abstract
Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.
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Affiliation(s)
- Eva L Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany
| | - Troels S Jensen
- Department of Neurology and Danish Pain Research Center, Aarhus University, 8000 Aarhus C, Denmark
| | - David L H Bennett
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK
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