Muscarinic acetylcholine receptor subtypes: physiological roles

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Allosteric modulation of -cell M3 muscarinic acetylcholine (ACh) receptors (M3Rs) greatly improves glucose homeostasis We previously demonstrated that M3Rs expressed by pancreatic -cells play a key role in stimulating insulin secretion and maintaining glucose homeostasis. For this reason, we examined whether a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. An advantage of allosteric muscarinic agents is that they respect the ACh-dependent spatio-temporal control of M3R activity. We found that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured -cells and mouse and human pancreatic islets. This response was absent in islets lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice, but not of mutant mice lacking M3Rs in -cells, stimulated insulin release in vivo, thus improving glucose tolerance. Importantly, VU0119498 treatment of pre-diabetic mice triggered enhanced insulin release and restored normal glucose tolerance. This proof-of-concept study strongly suggests that M3R PAMs may become clinically useful as novel antidiabetic agents. (Zhu L, Rossi M, Cohen A, Pham J, Zheng H, Dattaroy D, Mukaibo T, Melvin JE, Langel JL, Hattar S, Matschinsky FM, Appella DH, Doliba NM, Wess J. Allosteric modulation of -cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci USA 116, 18684-18690, 2019) The results summarized below were obtained in collaborative studies. Key role of M3Rs in the development of the cardiac conduction system To identify cellular pathways that regulate the development of the cardiac conduction system (CCS), we performed a compound screen in zebrafish embryos. This screen identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine treatment caused reduced heart rate, pericardial edema, and arrhythmia. Blockade of M3Rs induced changes in gene expression that led to the amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model further corroborated a role of M3Rs during cardiac progenitor specification and differentiation. These data indicate that M3Rs maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, thus preventing the development of arrhythmias. (Burczyk MS, Burkhalter MD, Tena TC, Grisanti LA, Kauk M, Matysik S, Donow C, Kustermann M, Rothe M, Cui Y, Raad F, Laue S, Moretti A, Zimmermann WH, Wess J, Khl M, Hoffmann C, Tilley DG, Philipp M. Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish. JCI Insight 4(20), pii: 121971, 2019) Muscarinic receptors regulate self-renewal of early erythroid progenitors The early erythroid progenitor, burst-forming unit erythroid (BFU-E), has the ability for self-renewal, thus serving as a key cell type for the treatment of anemias. We demonstrated that M4 muscarinic receptors (M4Rs) play a role in regulating BFU-E self-renewal and that pharmacological blockade of M4Rs corrects anemias of myelodysplastic syndrome (MDS), aging, and hemolysis. Muscarinic receptor antagonists were able to correct anemias in mouse models of MDS, aging, and hemolysis in vivo. The effects of muscarinic receptor blockade on promoting expansion of BFU-Es were mediated by enhanced activity of CREB which targets several key regulators of BFU-E self-renewal. These data identify muscarinic receptor antagonists as potential therapies for anemias associated with MDS, aging, and hemolysis. (Trivedi G, Inoue D, Chen C, Bitner L, Chung YR, Taylor J, Gnen M, Wess J, Abdel-Wahab O, Zhang L. Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors. Sci Transl Med 11(511), pii: eaaw3781, 2019) Reviews Zhu L, Rossi M, Doliba NM, Wess J. Beta-cell M3 muscarinic acetylcholine receptors as potential targets for novel antidiabetic drugs. Int Immunopharmacol 81:106267. doi: 10.1016/j.intimp.2020.106267 (Meeting Proceedings), 2020. Wess J. Muscarinic receptors. In "Encyclopedia of Molecular Pharmacology", 3nd ed., eds. S. Offermanns and W. Rosenthal, Springer, Berlin, 2020.