Sanjana Chauhan , Darrell R. Smith , Shiva Shariati-Ievari , Abhay Srivastava , Sanjiv Dhingra , Michel Aliani , Paul Fernyhough
{"title":"毒蕈碱乙酰胆碱1型受体拮抗剂激活TRPM3增强线粒体功能，驱动成人感觉神经元轴突修复。","authors":"Sanjana Chauhan , Darrell R. Smith , Shiva Shariati-Ievari , Abhay Srivastava , Sanjiv Dhingra , Michel Aliani , Paul Fernyhough","doi":"10.1016/j.molmet.2024.102083","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>Antagonism of the muscarinic acetylcholine type 1 receptor (M<sub>1</sub>R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M<sub>1</sub>R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.</div></div><div><h3>Methods</h3><div>Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M<sub>1</sub>R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca<sup>2+</sup> transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M<sub>1</sub>R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SH-SY5Y cells was conducted.</div></div><div><h3>Results</h3><div>M<sub>1</sub>R antagonism induced by PZ or MT7 increased Ca<sup>2+</sup> influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca<sup>2+</sup>. TRPM3 agonists elevated Ca<sup>2+</sup> levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M<sub>1</sub>R antagonism stimulated TRPM3 channel activity through inhibition of PIP<sub>2</sub> hydrolysis to activate Ca<sup>2+</sup>/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.</div></div><div><h3>Conclusions</h3><div>Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102083"},"PeriodicalIF":7.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732569/pdf/","citationCount":"0","resultStr":"{\"title\":\"Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons\",\"authors\":\"Sanjana Chauhan , Darrell R. Smith , Shiva Shariati-Ievari , Abhay Srivastava , Sanjiv Dhingra , Michel Aliani , Paul Fernyhough\",\"doi\":\"10.1016/j.molmet.2024.102083\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>Antagonism of the muscarinic acetylcholine type 1 receptor (M<sub>1</sub>R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M<sub>1</sub>R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.</div></div><div><h3>Methods</h3><div>Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M<sub>1</sub>R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca<sup>2+</sup> transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M<sub>1</sub>R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SH-SY5Y cells was conducted.</div></div><div><h3>Results</h3><div>M<sub>1</sub>R antagonism induced by PZ or MT7 increased Ca<sup>2+</sup> influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca<sup>2+</sup>. TRPM3 agonists elevated Ca<sup>2+</sup> levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M<sub>1</sub>R antagonism stimulated TRPM3 channel activity through inhibition of PIP<sub>2</sub> hydrolysis to activate Ca<sup>2+</sup>/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.</div></div><div><h3>Conclusions</h3><div>Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.</div></div>\",\"PeriodicalId\":18765,\"journal\":{\"name\":\"Molecular Metabolism\",\"volume\":\"92 \",\"pages\":\"Article 102083\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732569/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S221287782400214X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S221287782400214X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons
Objective
Antagonism of the muscarinic acetylcholine type 1 receptor (M1R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M1R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.
Methods
Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M1R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca2+ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M1R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP2) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SH-SY5Y cells was conducted.
Results
M1R antagonism induced by PZ or MT7 increased Ca2+ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca2+. TRPM3 agonists elevated Ca2+ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M1R antagonism stimulated TRPM3 channel activity through inhibition of PIP2 hydrolysis to activate Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.
Conclusions
Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.
期刊介绍：
Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction.
We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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