Modulation of GPCRs by monovalent cations and anions
- 437 Downloads
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.
KeywordsGPCR Monovalent cations Monovalent anions Modelling Pharmacology
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)).
- Coppini R, Ferrantini C, Mazzoni L, Sartiani L, Olivotto I, Poggesi C, Carbai E, Mugelli A (2013) Regulation of intracellular Na+ in health and disease: pathophysiological mechanism and implications for treatment. Glob Cardio / Sci Pract 3:222–242Google Scholar
- Gierschik P, Sidiropoulos D, Steisslinger M, Jakobs KH (1989) Na+ regulation of formyl peptide receptor-mediated signal transduction in HL60 cells. Evidence that the cation prevents activation of the G-protein by unoccupied receptors. Eur J Pharmacol (Mol Pharmacol) 172:481–492CrossRefGoogle Scholar
- Gierschik P, Moghtader R, Straub C, Dieterich K, Jakobs KH (1991) Signal amplification in HL-60 granulocytes: evidence that the chemotactic peptide receptor catalytically activates guanine-nucleotide-binding regulatory proteins in native plasma membranes. Eur J Biochem 197:725–732CrossRefPubMedGoogle Scholar
- Krautwurst D, Seifert R, Hescheler J, Schultz G (1992) Formyl peptides and ATP stimulate Ca2+ and Na+ inward currents through non-selective cation channels via G-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells. Involvement of Ca2+ and Na+ in the activation of beta-glucuronidase release and superoxide production. Biochem J 288(Pt 3):1025–1035PubMedCentralPubMedGoogle Scholar
- Selent J, Sanz F, Pastor M, De Fabritiis G (2010) Induced effects of sodium ions on dopaminergic G-protein coupled receptors. PLOS Comput Chem 6:e10000884Google Scholar
- Vosahlikova M, Jurkiewicz P, Roubalova L, Hof M, Svoboda P (2014) High- and low-affinity sites for sodium in δ-OR-Gi1α (Cys351-Ile351) fusion protein stably expressed in HEK293 cells; functional significance and correlation with biophysica state of the plasma membrane. Naunyn Schmiedebergs Arch Pharmacol 387:487–502CrossRefPubMedGoogle Scholar