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 i...
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782400214X |
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| author | Sanjana Chauhan Darrell R. Smith Shiva Shariati-Ievari Abhay Srivastava Sanjiv Dhingra Michel Aliani Paul Fernyhough |
| author_facet | Sanjana Chauhan Darrell R. Smith Shiva Shariati-Ievari Abhay Srivastava Sanjiv Dhingra Michel Aliani Paul Fernyhough |
| author_sort | Sanjana Chauhan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-22d1efaeb0a74d39995b721e267533a0 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-22d1efaeb0a74d39995b721e267533a02025-02-01T04:11:56ZengElsevierMolecular Metabolism2212-87782025-02-0192102083Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neuronsSanjana Chauhan0Darrell R. Smith1Shiva Shariati-Ievari2Abhay Srivastava3Sanjiv Dhingra4Michel Aliani5Paul Fernyhough6Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, CanadaDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, CanadaDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, CanadaInstitute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, CanadaInstitute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, CanadaDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, CanadaDivision of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Canada; Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Corresponding author. Department of Pharmacology & Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Director, Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, R4046 – 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada.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.http://www.sciencedirect.com/science/article/pii/S221287782400214XAxonal regenerationBioenergeticsDiabetic neuropathyGPCRMetabolomicsMitochondria |
| spellingShingle | Sanjana Chauhan Darrell R. Smith Shiva Shariati-Ievari Abhay Srivastava Sanjiv Dhingra Michel Aliani Paul Fernyhough Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons Molecular Metabolism Axonal regeneration Bioenergetics Diabetic neuropathy GPCR Metabolomics Mitochondria |
| title | Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| title_full | Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| title_fullStr | Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| title_full_unstemmed | Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| title_short | Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| title_sort | muscarinic acetylcholine type 1 receptor antagonism activates trpm3 to augment mitochondrial function and drive axonal repair in adult sensory neurons |
| topic | Axonal regeneration Bioenergetics Diabetic neuropathy GPCR Metabolomics Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S221287782400214X |
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