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.
Highlights
The GPR4 receptor is widely expressed in different tissues and was initially described to be a proton-sensing G-protein coupled receptors (GPCRs) by Ludwig et al in 2003 [1]
It was observed that OGR1 expressed in human airway smooth muscle cells (ASMC) seems to mediate the synthesis of the proinflammatory cytokines interleukin 6 (IL-6), IL-8 and increase of intracellular calcium concentrations upon acidic pH stimulation, which may subsequently lead to enhanced formation of extracellular matrix proteins and increase the expression of connective tissue growth factor (CTGF) [9,92]
G2A seems to differ profoundly from the other proton-sensing GPRCs in many respects: first, it has the weakest sequence similarity and shows the weakest activation by protons. It is activated by oxidized fatty acid derivatives. It has distinct roles in immune cell migration, hematopoiesis, and neuropathic pain that are unique in the group of proton-sensing GPCRs and make it an interesting therapeutic target in related disease states (Figure 2)
Summary
The family of proton-sensing G-protein coupled receptors (GPCRs) has first been described by Ludwig et al in 2003 and consists of four members that belong to the class A orphan GPCRs: GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132) [1,2,3]. The GPR4 receptor is widely expressed in different tissues and was initially described to be a proton-sensing GPCR by Ludwig et al in 2003 [1] It is activated over a broad pH range from 5.6–7.6 and shares all the crucially involved histidine residues with OGR1. It was observed that OGR1 expressed in human airway smooth muscle cells (ASMC) seems to mediate the synthesis of the proinflammatory cytokines interleukin 6 (IL-6), IL-8 and increase of intracellular calcium concentrations upon acidic pH stimulation, which may subsequently lead to enhanced formation of extracellular matrix proteins and increase the expression of connective tissue growth factor (CTGF) [9,92]. It is activated by oxidized fatty acid derivatives It has distinct roles in immune cell migration, hematopoiesis, and neuropathic pain that are unique in the group of proton-sensing GPCRs and make it an interesting therapeutic target in related disease states (Figure 2).
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