Proton-Sensing GPCRs in Health and Disease

Abstract

The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.

Keywords: G2A; GPCR; GPR4; OGR1; TDAG8; inflammation; neuropathic pain; pain; proton-sensing GPCR; tumor microenvironment.

Figure 1

pH activation range in vitro, coupling preferences and signaling of the four proton-sensing GPCRs. The individual pH activation range for each of the four receptors TDAG8 (GPR65, green), G2A (GPR132, blue), GPR4 (yellow), and OGR1 (GPR68, red) is shown above. The pH ranges were determined in heterologous expression systems using various cell lines and are obtained from [1,5,42]. The receptors can couple to different G-proteins (G_S, G_12/13, G_q, G_i). The coupling preferences for each receptor differ depending on the investigated cell type, tissue, and the physiological or pathophysiological state, and were obtained from [1,8,9,10,11,14,43,44,45]. Abbreviations: AC: adenylyl cyclase, cAMP: cyclic adenosine monophosphate, Rho: Ras homologue, ROCK: Rho-associated coiled-coil-containing protein kinase, PLC: phospholipase C, PKC: protein kinase C, [Ca²⁺]_i: intracellular calcium concentration, Ras: rat sarcoma protein, MAPK: mitogen-activated protein kinase(s), PI3K: phosphoinositide 3-kinase, Akt: protein kinase B, LPAR: lysophosphatidic acid receptor, S1PR: sphingosine-1-phosphate receptor.

Figure 2

Individual and overlapping physiological and pathophysiological properties of the four proton-sensing GPCRs. GPR4 (yellow), TDAG8 (GPR65, green), G2A (GPR132, blue), and OGR1 (GPR68, red). The figure visualizes functional overlaps between the proton-sensitive GPCRs. The actual pairwise overlap between these receptors in sensory neurons has been demonstrated previously [55]. Abbreviations: ER: endoplasmic reticulum, cAMP: cyclic adenosine monophosphate, DRG: dorsal root ganglia, LPS: lipopolysaccharide, IL-6: interleukin 6, TNFα: tumor necrosis factor α, TME: tumor microenvironment, SMC: smooth muscle cells, COX-2: cyclooxygenase-2, PGI₂: prostaglandin I₂.

Figure 3

Potential therapeutic effects of agonists and antagonists of the four proton-sensing GPCRs. GPR4 (yellow), TDAG8 (GPR65, green), G2A (GPR132, blue), and OGR1 (GPR68, red). Abbreviations: ER: endoplasmic reticulum, IL-6: interleukin 6, TNFα: tumor necrosis factor α, PGI₂: prostaglandin I₂, IL-8: interleukin 8.