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 res-idues. 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 de-tect acidic cellular environments in the context of inflammation, recent observations have expand-ed our knowledge about their physiological and pathophysiological functions and many addition-al 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 as-pects of tumor biology, cardiovascular physiology, and asthma. However, apart from their over-lapping functions, they seem to have individual properties, and recent publications identify po-tential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunologi-cal interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put to-gether 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 ex-plore all currently known pharmacological modulators of the four receptors and highlight poten-tial use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton‐sensing GPCRs that should be addressed by future studies.