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Modulation of GPCRs by monovalent cations and anions

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Abstract

The recent resolution of G-protein-coupled receptor (GPCR) structures in complex with Na+ bound to an allosteric modulatory site has renewed interest of the regulation of GPCRs by ions. Here, we summarise key data on ion modulation of GPCRs, obtained in pharmacological, crystallographic, mutagenesis and molecular modelling studies. We show that ion modulation is a highly complex process, involving not only cations but also, rather neglected until now, anions. Pharmacotherapeutic and toxicological aspects are discussed. We provide a mathematical framework for the analysis of ion effects. Finally, we discuss open questions in the field and future research directions. Most importantly, the in vivo relevance of the modulation of GPCR function by monovalent ions must be clarified.

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Acknowledgments

We acknowledge the collaboration with Dr. D. Schnell, in the hH3R project. This work was supported by grants of the Deutsche Forschungsgemeinschaft (GRK 1910, GRK 1441, SFB 587) and the European Union (COST programme BM0806 (H4R network)).

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Authors and Affiliations

  1. Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany

    Andrea Strasser

  2. Faculty of Chemistry/Pharmacy, University of Regensburg, Regensburg, Germany

    Hans-Joachim Wittmann

  3. Institute of Pharmacology, Medical School of Hannover, Hannover, Germany

    Erich H. Schneider & Roland Seifert

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  1. Andrea Strasser
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  2. Hans-Joachim Wittmann
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  3. Erich H. Schneider
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  4. Roland Seifert
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Correspondence to Andrea Strasser.

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Strasser, A., Wittmann, HJ., Schneider, E.H. et al. Modulation of GPCRs by monovalent cations and anions. Naunyn-Schmiedeberg's Arch Pharmacol 388, 363–380 (2015). https://doi.org/10.1007/s00210-014-1073-2

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