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Muscarinic acetylcholine receptors: novel opportunities for drug development

Nature Reviews Drug Discovery volume 13, pages 549–560 (2014)Cite this article

Subjects

Key Points

  • The five muscarinic acetylcholine receptors (mAChRs) are prototypical class A G protein-coupled receptors (GPCRs).

  • mAChRs regulate many fundamental functions of the central and peripheral nervous system.

  • Recent studies with novel mAChR mouse models have provided detailed insights into the physiological roles of the different mAChR subtypes (M1 to M5).

  • High-resolution structural information is now available for the M2 and M3 receptors, providing a structural basis for mAChR activation and the binding of different types of muscarinic ligands, including allosteric modulators.

  • These new findings should facilitate the development of novel drugs targeting muscarinic receptors for the treatment of many severe pathophysiological conditions.

Abstract

The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions.

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Figure 1: Modes of targeting mAChRs (GPCRs) by different classes of ligands.
Figure 2: Overall structure of the M2 and M3 receptors.
Figure 3: Structure of the orthosteric mAChR ligand binding site.
Figure 4: Activation and allosteric modulation of the M2 receptor.
Figure 5: Hypothetical mechanism for allosteric modulation of the M2 receptor by a PAM.

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Acknowledgements

We apologize to all investigators whose important contributions could not be acknowledged owing to space limitations. The work of A.C.K. and B.K.K. was supported by a US National Science Foundation Graduate Research Fellowship (A.C.K.) and by the National Science Foundation grant CHE-1223785 and US National Institutes of Health (NIH) grant U19GM106990 (B.K.K.). A.C. and P.M.S. received funds from Program Grant No. APP1055134 of the National Health and Medical Research Council (NHMRC) of Australia. A.C. and P.M.S. are NHMRC Principal Research Fellows. The research of D.G. and J.W. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH. We thank all our co-workers and collaborators for their invaluable contributions to the work summarized in this Review.

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  1. Andrew C. Kruse

    Present address: Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.,

Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Andrew C. Kruse & Brian K. Kobilka

  2. Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, 20892–0810, Maryland, USA

    Dinesh Gautam & Jürgen Wess

  3. Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, 3052, Victoria, Australia

    Patrick M. Sexton & Arthur Christopoulos

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Correspondence to Jürgen Wess.

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Kruse, A., Kobilka, B., Gautam, D. et al. Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13, 549–560 (2014). https://doi.org/10.1038/nrd4295

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