GPR68 Membrane Protein Introduction

Introduction of GPR68

G-protein coupled receptor 68, also known as Ovarian cancer G-protein coupled receptor 1 (OGR-1) or Sphingosylphosphorylcholine receptor, is a protein that in humans is encoded by the GPR68 gene. It belongs to the subfamily of G-protein-coupled receptor which is composed of four members: OGR1, GPR4, G2A, and TDAG8. Studies have shown that all members of ovarian cancer G-protein-coupled-receptor subfamily have proton-sensing activity and are regulated by certain lipid molecules.

Function of GPR68 Membrane Protein

G protein-coupled receptors (GPCRs), the largest family of cell signaling receptors, are 7 transmembrane receptors that respond to numerous types of extracellular signals and regulate many physiologic processes. It has been reported that GPR68, along with other members of the OGR1-family of G protein-coupled receptors (GPCRs), are sensors of the mild decreases in extracellular pH that occur under inflammatory conditions. Recently, studies have shown that GPR68 is expressed in various immune cells including macrophages, dendritic cells, T cells, and neutrophils and has a pro-inflammatory function in various disease states. For example, OGR1-deficient mice (herein referred to as OGR1-KO mice) exhibit less severe airway inflammation in the ovalbumin (OVA)-induced sensitization/challenge model of asthma. It has been also reported that syngeneic melanoma and prostate cell lines do not grow or engraft as well in OGR1-KO mice as a result of the higher tumoricidal activity of macrophages. Furthermore, decreases in pH have been shown to trigger the OGR1-dependent increase in IL-6 secretion by human airway smooth muscle cells in vitro.

Fig.1 Activation of ovarian cancer G protein-coupled receptor 1 (OGR1) by extracellular acidification. (A) Proton has been suggested as agonists of OGR1. Cu²⁺ and Zn²⁺ inhibit pH-dependent OGR1 activation, and (B) His residues that have been reported to be involved in the proton-sensing process are bolded and underlined in OGR1. (Yuan, 2014)

Application of GPR68 Membrane Protein in Literature

1. Xu J., et.al. GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell. 2018, 173(3):762-75. PubMed ID: 29677517
   
   

   This article suggests that GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.

2. Wiley S.Z., et.al. GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells. The FASEB Journal. 2018, 32(3):1170-83. PubMed ID: 29092903
   
   

   This article suggests that cancer-associated fibroblasts-expressed GPR68 is a mediator of low-pH-promoted regulation of the tumor microenvironments, in particular to pancreatic ductal adenocarcinoma cell-CAF interaction and may be a novel therapeutic target for pancreatic and perhaps other types of cancers.

3. Parry D.A., et.al. Mutations in the pH-sensing G-protein-coupled receptor GPR68 cause amelogenesis imperfecta. The American Journal of Human Genetics. 2016, 99(4):984-90. PubMed ID: 27693231
   
   

   This article indicates that GPR68 plays a role as a proton sensor that is required for proper enamel formation.

4. de Vallière C., et.al. Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein-Coupled Receptor OGR1 (GPR68). Cellular and molecular gastroenterology and hepatology. 2016, 2(6):796-810. PubMed ID: 28174749
   
   

   This article is conducted to investigate how hypoxia regulates the expression of OGR1 in the intestinal mucosa and associated cells. It suggests that the enhancement of TNF- and hypoxia-induced OGR1 expression under low pH points to a positive feed-forward regulation of OGR1 activity in acidic conditions, and supports a role for OGR1 in the pathogenesis of inflammatory bowel disease (IBD).

5. Chandra V., et.al. Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells. Scientific reports. 2016, 6:25765. PubMed ID: 27166427
   
   

   This article provides a mechanistic insight into GPR68 mediate β-cell response to acidic microenvironment, which could be a new target to protect β-cell against acidosis induced inflammation.

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Reference

1. Yuan, et.al. (2014). Molecular actions of ovarian cancer G protein-coupled receptor 1 caused by extracellular acidification in bone. International journal of molecular sciences. 15(12), 22365-22373.

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