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.
Highlights
Acid–base balance is mainly maintained by the action of the kidneys and lungs that respond to changes in acid–base conditions by controlling the levels of buffers in the blood and by pacing the elimination of acids and bases
These receptors belong to different types of proteins, in which the most well-studied are as follows: (1) ion channels, such as acidsensing ion channels (ASIC) [8], the renal outer medullary K+ channel (ROMK) [101], TWIK-related acid-sensitive K+ channel (TASK) [6], and transient receptor potential channels (TRP) [87]; (2) tyrosine kinases, such as insulin receptor–related receptor (IRRR) [14]; and (3) G protein–coupled receptors (GPCRs), the topic of this review
We have investigated the bones of 16-week-old OGR1-deficient mice and we did not find microstructural abnormalities at baseline and after 4 and 8 weeks of acid loading with N H4Cl in both male and female mice [44] using the same model as Krieger et al in [60])
Summary
Acid–base balance is mainly maintained by the action of the kidneys and lungs that respond to changes in acid–base conditions by controlling the levels of buffers in the blood and by pacing the elimination of acids and bases. The increase in intracellular calcium induced by shear stress observed in a breast cancer cell line was mostly absent at pH values below 6 and above 8, demonstrating that mechanosensing via OGR1 requires pH values in the same range as for its activation by protons [147] Both works show that OGR1 is a coincidence sensor for pH and mechanostimuli, e.g., both stimuli are concomitantly essential for the normal activity of OGR1, a seemingly unique feature among GPCRs. While extensive research on the role of GPR4 and TDAG8 in physiology and pathophysiology has been done, they are understudied when it comes to investigate their basic properties, such as their regulation at molecular level and downstream signaling. There are technical and/or biological issues that have been hampering this research field and may require special attention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
