Physiological relevance of proton-activated GPCRs

Abstract

The detection of H⁺ concentration variations in the extracellular milieu is accomplished by a series of specialized and non-specialized pH-sensing mechanisms. The proton-activated G protein-coupled receptors (GPCRs) GPR4 (Gpr4), TDAG8 (Gpr65), and OGR1 (Gpr68) form a subfamily of proteins capable of triggering intracellular signaling in response to alterations in extracellular pH around physiological values, i.e., in the range between pH 7.5 and 6.5. Expression of these receptors is widespread for GPR4 and OGR1 with particularly high levels in endothelial cells and vascular smooth muscle cells, respectively, while expression of TDAG8 appears to be more restricted to the immune compartment. These receptors have been linked to several well-studied pH-dependent physiological activities including central control of respiration, renal adaption to changes in acid-base status, secretion of insulin and peripheral responsiveness to insulin, mechanosensation, and cellular chemotaxis. Their role in pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), and tumor cell metabolism and invasiveness, is increasingly receiving more attention and makes these receptors novel and interesting targets for therapy. In this review, we cover the role of these receptors in physiological processes and will briefly discuss some implications for disease processes.

Keywords: Acid–base balance; Bone; Cell signaling; Inflammation; Kidney; Respiration; pH sensing.

Fig. 1

Summary of activators and modulators of proton-activated GPCRs and the Gα subunits coupled to these receptors. Extracellular histidine residues (eHis) and a buried triad of amino acids have been proposed as the mechanisms underlying proton sensitivity in these receptors. Asp, aspartic acid; Glu, glutamic acid

Fig. 2

Summary of the main physiological roles of proton-activated GPCR. RTN, retrotrapezoid nucleus; SFO, subfornical organ; RANKL, receptor activator of nuclear factor-kappa B ligand