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Novel Insights into M3 Muscarinic Acetylcholine Receptor Physiology and Structure

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Abstract

Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential.

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Acknowledgments

The structural studies summarized in this review were supported by US National Science Foundation (NSF) grant CHE-1223785 and a gift from the Mathers Charitable Foundation (to B.K.K.). A.C.K. was funded by a National Science Foundation Graduate Research Fellowship. The work of J.L., J.H., and J.W. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. We thank all of our coworkers and collaborators for their invaluable contributions to the work summarized in this minireview.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA

    Andrew C. Kruse & Brian K. Kobilka

  2. Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bldg. 8A, Room B1A-05, 8 Center Drive, Bethesda, MD, 20892, USA

    Jianhua Li, Jianxin Hu & Jürgen Wess

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  1. Andrew C. Kruse
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Correspondence to Jürgen Wess.

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Kruse, A.C., Li, J., Hu, J. et al. Novel Insights into M3 Muscarinic Acetylcholine Receptor Physiology and Structure. J Mol Neurosci 53, 316–323 (2014). https://doi.org/10.1007/s12031-013-0127-0

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