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Muscarinic Receptor: From Structure to Animal Models pp 95–130Cite as

Allosteric Modulation of Muscarinic Receptors

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Part of the book series: Neuromethods ((NM,volume 107))

Abstract

Allosteric ligands modulate binding and function of muscarinic receptors in a different way than orthosteric ligands. Unlike orthosteric ligands their effects are limited by a cooperativity factor. This imparts them unique properties, including cooperativity-based selectivity, functional selectivity and restoring of physiological-like space and time pattern of signaling under pathological conditions. Therefore, allosteric modulators of muscarinic receptor are intensively studied as possible therapeutics of pathological conditions including Alzheimer’s disease and schizophrenia. Research of allosteric modulation has pioneered the way for a whole class A of G-protein coupled receptors and has had an impact beyond its own field. We review principles of allosteric modulations and their implications for proper design of binding as well as functional experiments and for proper data analysis. We demonstrate immense complexity of allosteric modulation of functional responses. Such complexity is reflected in the inability to determine individual microscopic constants in allosterically modulated systems. Therefore, the effects of a given allosteric modulator can be characterized by only two macroscopic parameters, namely a change in the agonist potency and efficacy. We also discuss distinct properties of allosteric interactions that are specific to muscarinic receptors.

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Acknowledgments

This research was supported by Academy of Sciences of the Czech Republic support RVO: 67985823 and Grant Agency of the Czech Republic grant P304/12/G069.

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Authors and Affiliations

  1. Department of Neurochemistry, Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220, Prague, Czech Republic

    Jan Jakubik

  2. Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, 55455, USA

    Esam E. El-Fakahany

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  1. Jan Jakubik
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  2. Esam E. El-Fakahany
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Correspondence to Jan Jakubik .

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Editors and Affiliations

  1. Institute of Physiology, Charles University, Prague, Czech Republic

    Jaromir Myslivecek

  2. Department of Neurochemistry, Acad. of Sciences of the Czech Rep. Institute of Physiology, Prague, Czech Republic

    Jan Jakubik

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Jakubik, J., El-Fakahany, E.E. (2016). Allosteric Modulation of Muscarinic Receptors. In: Myslivecek, J., Jakubik, J. (eds) Muscarinic Receptor: From Structure to Animal Models. Neuromethods, vol 107. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2858-3_6

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  • DOI: https://doi.org/10.1007/978-1-4939-2858-3_6

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2857-6

  • Online ISBN: 978-1-4939-2858-3

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