Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Abstract

Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model

“…No biochemical changes in individuals with various genotypes of rs8005161 were observed, but we observed a lower activation of RhoA upon an acidic pH shift in IBD patients 23 . These studies suggest that TDAG8 negatively regulates inflammation in IBD; supporting the notion of an anti-inflammatory role for TDAG8 14,30,31 .…”

Can GPR4 Be a Potential Therapeutic Target for COVID-19?

“…As the disease severity of COVID-19 progresses, alveolar epithelial and endothelial barriers become disrupted, oxygen/carbon dioxide exchange is impaired, and the lung tissues become hypoxic. The pH of inflammatory and hypoxic tissues is acidic due to reduced oxygen levels, glycolytic cell metabolism, and proton accumulation (27,28,(34)(35)(36). In addition to acidotic pH in inflamed and hypoxic tissues, respiratory and metabolic acidosis is a common complication observed in COVID-19 patients, especially in patients with severe disease (37).…”

GPR4 knockout attenuates intestinal inflammation and forestalls the development of colitis-associated colorectal cancer in murine models

“…Patients with IBD are at a ~ 2.4 fold higher risk for developing colitis associated colorectal cancer (CAC) due to persistent and unresolved intestinal inflammation [2]. Local tissue acidosis exists in the inflammatory loci and is owing in part to shifts in hypoxia, glycolytic cellular metabolism, production of bacterial metabolic byproducts, and granulocyte respiratory bursts [6,7,8,50]. Increased proton concentrations in the extracellular milieu can activate GPR4 by protonation of histidine residues on the extracellular domain and initiate activation of downstream G protein pathways [51].…”

“…A family of proton-sensing G protein-coupled receptors (GPCR) capable of sensing changes in extracellular pH have recently been implicated in regulating intestinal inflammation. The pHsensing GPCR family includes GPR4, GPR65, and GPR68 of which are activated by protonation of histidine residues on the receptor extracellular domains [7,10,11,12,13,14,15]. GPR4 is predominately expressed on vascular endothelial cells among other cell types [16,17,18,19,20,21,22].…”