Muscarinic acetylcholine receptor subtypes: physiological roles

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

SUMMARY Ongoing studies focus on the roles of the different mAChR subtypes in the regulation of key metabolic functions, with particular focus on glucose and energy homeostasis. Such functions include the release of incretins from enteroendocrine cells and the secretion of insulin and glucagon from pancreatic beta- and alpha-cells, respectively. We are also studying the potential regulation of food intake and body weight by mAChRs expressed in distinct neurons of the hypothalamus. We are currently generating cell type-specific mAChR mutant mice to elucidate the physiological and pathophysiological roles of distinct mAChRs expressed by these metabolically critical cell types. The outcome of these studies may pave the way toward the development of novel muscarinic drugs that may prove useful for the treatment of obesity and type 2 diabetes. Work published in collaboration with the lab of Dr. Alexander Gourine: Exercise capacity is under the control of cardiovascular and respiratory responses regulated by the autonomic nervous system. High exercise capacity correlates with a low resting heart rate, an indirect marker of increased parasympathetic (vagal) tone. On the other hand, impaired exercise capacity is associated with vagal autonomic dysfunction. The mechanisms by which vagal parasympathetic activity modulate exercise capacity remain unclear. ACh released from peripheral parasympathetic nerve endings exerts its physiological effects by activating primarily M2 and M3 mAChRs. In a recent study, we used a series of constitutive and cell type-specific M2 and M3 mAChR mutant mice to explore the role of M2 and M3 mAChR signaling in regulating exercise capacity. We found that the M3 mAChR expressed by vascular endothelial cells plays an important physiological role in optimizing exercise capacity. Most likely, vascular M3 mAChRs in skeletal muscle are critical for ensuring enhanced blood flow during exercise. This new finding has the potential to stimulate the development of novel therapeutic agents targeting the M3 mAChR to improve exercise capacity. recent ref: Ackland GL, Hosford PS, Gutierrez del Arroyo A, Korsak A, Machhada A, Pickard J, Stuckey DJ, Tinker A, Tobin AB, Jeon J, Wess J, Gourine AV. The physiological significance of endothelial M3 muscarinic receptors during exercise. Circ Res doi: 10.1161/ CIRCRESAHA.125.326589. Online ahead of print, July 2025.