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

Authors Sanderlin E, Justus C, Krewson E, Yang L

Received 19 November 2014

Accepted for publication 15 January 2015

Published 2 March 2015 Volume 2015:7 Pages 99—109

DOI https://doi.org/10.2147/CHC.S60508

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Professor Denis Wirtz


Edward J Sanderlin,1 Calvin R Justus,1 Elizabeth A Krewson,2 Li V Yang1,2

1Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA; 2Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

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 Gs, Gq/11, and G12/13 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.


Keywords: acidosis, GPCR, GPR4, GPR65 (TDAG8), GPR68 (OGR1)

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