GPR65 Membrane Protein Introduction

Introduction of GPR65

G-protein coupled receptor 65, also known as Psychosine receptor or T-cell death-associated gene 8 protein (TDAG8), is a protein that in humans is encoded by the GPR65 gene. It belongs to the sub-family of proton-sensing receptors. Other members of this family include GPR4, GPR68, and GPR132. Proteins of this family were originally characterized as receptors for lipid messengers such as sphingosylphosphorylcholine (SPC), lysophosphatidylcholine (LPC) and psychosine. During the past years, a series of studies have been conducted to investigate the functions and applications of this protein.

Function of GPR65 Membrane Protein

G protein-coupled receptors (GPRs) are seven-transmembrane domains receptors involved in a wide variety of physiological processes in humans, and they are targets of many drugs. As a member of GPRs, GPR65 is a specific receptor for psychosine as well as several other related glycosphingolipids. Studies have shown that GPR65 is predominantly expressed in lymphoid tissues, including spleen, lymph nodes, thymus, and leukocytes, and contributes to multinuclear formation and apoptosis in the cell. Recently, GPR65 has been reported to inhibit osteoclastic bone resorption in a mouse model of ovariectomy by sensing the acidic extracellular milieu. Furthermore, GPR65 might be involved in the regulation of tumor growth by supporting cell survival in such acidic conditions. It has also been shown that overexpression of GPR65 in Lewis lung carcinoma cells could increase tumor growth in mice possibly through evasion of acidosis-induced cell death. Similarly, overexpression of GPR65 might malignantly transform mammary epithelial cells and acidic activation of GPR65 protein may render lymphoma cell lines resistant to apoptosis under stress conditions, which indicating that GPR65 may act as a prosurvival factor in an acidic environment.

Fig.1 Biological roles and G protein coupling of the pH-sensing GPCRs. (Sanderlin, 2015)

Application of GPR65 Membrane Protein in Literature

1. Wirasinha R.C., et.al. GPR 65 inhibits experimental autoimmune encephalomyelitis through CD 4+ T cell-independent mechanisms that include effects on iNKT cells. Immunology and cell biology. 2018, 96(2):128-36. PubMed ID: 29363187
   
   

   This article aims to evaluate whether GPR65 plays a functional role in demyelinating autoimmune disease. It suggests that there is an association between GPR65 and multiple sclerosis. Also, GPR65 signals could suppress autoimmune activity in experimental autoimmune encephalomyelitis.

2. Ail D., et.al. Increased expression of the proton-sensing G protein-coupled receptor Gpr65 during retinal degeneration. Neuroscience. 2015, 301:496-507. PubMed ID: 26117715
   
   

   This research was conducted to investigate the expression and function of these proton-sensing GPRs in the normal and degenerating retina. It indicates that the proton-sensing G protein-coupled receptor GPR65 may be involved in a mechanism that supports the survival of photoreceptors in the degenerating retina.

3. Ahn S.H., et.al. Psychosine inhibits osteoclastogenesis and bone resorption via G protein-coupled receptor 65. Journal of endocrinological investigation. 2015, 38(8):891-9. PubMed ID: 25841894
   
   

   This article aims to investigate the role of the lysosphingolipid psychosine, a GPR65 ligand, on osteoclastic differentiation and bone resorption. It suggests that psychosine could inhibit osteoclastogenesis by increasing intracellular cAMP levels through GPR65.

4. Rosko A.E., et.al. Acidosis sensing receptor GPR65 correlates with anti-apoptotic Bcl-2 family member expression in CLL cells: potential implications for the CLL microenvironment. Journal of leukemia. 2014, 2(5). PubMed ID: 25984552
   
   

   This article finds that the acid-sensing receptor GPR65 may be of significance to allow CLL tolerance of extracellular acidosis. Moreover, the correlation of GPR65 with Bcl-2 suggests a novel cytoprotective mechanism that enables CLL cell adaptation to acidic extracellular conditions, which suggests the potential value of targeting GPR65 therapeutically.

5. Zhu X., et.al. Differential eosinophil and mast cell regulation: mast cell viability and accumulation in inflammatory tissue are independent of proton-sensing receptor GPR65. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2014, 306(11): G974-82. PubMed ID: 24742990
   
   

   This article demonstrates that differential regulation of eosinophils and mast cells in inflammatory tissue, with mast cell viability and accumulation being independent of GPR65.

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Reference

1. Sanderlin, et.al. (2015). Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress. CELL HEALTH AND CYTOSKELETON. 7, 99-109.

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