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Structure–Function Studies of Muscarinic Acetylcholine Receptors

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Book cover Muscarinic Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 208))

Abstract

There has been great interest in the structure–function relationships of the muscarinic acetylcholine receptors (mAChRs) because these prototypical Family A/class 1 G protein-coupled receptors (GPCRs) are attractive therapeutic targets for both peripheral and central nervous system disorders. A multitude of drugs that act at the mAChRs have been identified over the years, but many of these show minimal selectivity for any one of the five mAChR subtypes over the others, which has hampered their development into therapeutics due to adverse side effects. The lack of drug specificity is primarily due to high sequence similarity in this family of receptor, especially in the orthosteric binding pocket. Thus, there remains an ongoing need for a molecular understanding of how mAChRs bind their ligands, and how selectivity in binding and activation can be achieved. Unfortunately, there remains a paucity of solved high-resolution structures of GPCRs, including the mAChRs, and thus most of our knowledge of structure–function mechanisms related to this receptor family to date has been obtained indirectly through approaches such as mutagenesis. Nonetheless, such studies have revealed a wealth of information that has led to novel insights and may be used to guide future rational drug design campaigns.

Katie Leach and John Simms contributed equally to the work.

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Notes

  1. 1.

    At the time of writing, the crystal structures of antagonist-bound chemokine CXCR4 and dopamine D3 receptors have been solved but not published.

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Acknowledgments

Work shown from the authors’ laboratory is funded by Program Grant No. 519461 of the National Health and Medical Research Council (NHMRC) of Australia. AC is a Senior, and PMS a Principal, Research Fellow of the NHMRC.

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Authors and Affiliations

  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia

    Katie Leach, John Simms, Patrick M. Sexton & Arthur Christopoulos

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  1. Katie Leach
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  2. John Simms
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  3. Patrick M. Sexton
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  4. Arthur Christopoulos
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Correspondence to Arthur Christopoulos .

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Editors and Affiliations

  1. UHN67, Department of Pulmonary and Critical Ca, Oregon Health & Science University, SW Sam Jackson Park Road 3181, Portland, 97239, Oregon, USA

    Allison D. Fryer

  2. , Department of Pharmacology, Monash Institute of Pharmaceutical Scien, Royal Parade 381, Parkville, 3052, Victoria, Australia

    Arthur Christopoulos

  3. , Department of Pharmacology, University of Washington, Seattle, 98195-7750, Washington, USA

    Neil M. Nathanson

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© 2012 Springer-Verlag Berlin Heidelberg

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Leach, K., Simms, J., Sexton, P.M., Christopoulos, A. (2012). Structure–Function Studies of Muscarinic Acetylcholine Receptors. In: Fryer, A., Christopoulos, A., Nathanson, N. (eds) Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9_2

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