Modulation of GPCRs by monovalent cations and anions

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.

Dynamic monitoring of Gi/o-protein-mediated decreases of intracellular cAMP by FRET-based Epac sensors

“…GPCRs are commonly activated by a plethora of small molecules and hormones, and some GPCRs can even perceive physical and chemical cues such as mechanical forces (summarized in [28]), voltage [2, 3, 22, 23], or ions [29]. Since GPCRs are involved in many physiological and pathophysiological processes and represent molecular targets for about 30% of all approved drugs [20], a detailed analysis of GPCRs and their signaling pathways is of utmost importance and may be leveraged to further improve medical treatment.…”

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

“…For instance, the conformation of the binding site may be influenced by whether or not the receptor is contained in a lipid raft; interacting with RGS proteins, GRKs, and other molecules; in proximity to the G protein; phosphorylated; glycosylated; ubiquitinated; or palmitoylated (Alonso and Friedman, 2013; Chini and Parenti, 2009; Gahbauer and Böckmann, 2016; Vošahlíková and Svoboda, 2011; Wisler et al, 2014; Zheng et al, 2013). DORs also have a large Na + pocket in their inactive state that affects ligand binding and coupling to downstream signaling pathways (Appelmans et al, 1986; Fenalti et al, 2014; Strasser et al, 2015). This Na + pocket is affected by V m , decreasing the probability that it occupies its allosteric binding site and moving to the orthosteric ligand binding site as V m increases (Vickery et al, 2016), therefore the local membrane electrical and ionic environments at individual receptors may influence pharmacological responses as well.…”

Lithium – therapeutic tool endowed with multiple beneficiary effects caused by multiple mechanisms

“…Limitation of the studies conducted with the effect of Li + on GPCRs in vitro was the fact that Li + was studied alone and not in competition with Na + or K + (Gierschik et al 1991, Seifert 2001. In similarity with conventional GPCR ligands, GPCR-specific structure-activity relationships for various cations are emerging at present time (Strasser et al 2015). It can be suggested that there is a rising preference for binding of a monovalent cation in the so-called Hofmeister (1888) series Cs + → Rb + → K + → Na + → Li + .…”

“…Thus, in similarity with conventional GPCR ligands, GPCR-specific structure-activity relationships for various cations are emerging (Strasser et al 2015). Based on these data, it can be suggested that there is a rising preference for binding of a monovalent cation in the Hofmeister (1888) series Cs…”