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 group of Dr. Christian Alzheimer: mAChRs play key roles in hippocampus-dependent learning and memory. Hippocampal slices obtained from M1/M3 mAChR KO mice showed enhanced long-term potentiation (LTP) but greatly reduced long-term depression (LDP). In contract, deletion of M2 mAChRs augmented both LTP and LTD in this preparation. These data indicate that M1/M3 and M2 mAChRs regulate LTP and LTD at hippocampal mossy fiber-CA3 pyramidal cell synapses in a synergistic and antagonistic fashion, respectively. REF: Zheng F, Wess J, Alzheimer C. M1/M3 muscarinic acetylcholine receptors control long-term, but not short-term plasticity at the mossy fiber - CA3 pyramidal cell synapse in mouse hippocampus. Cells 12(14), 1890, 2023.