SPC/LPC/Proton-sensor Family Related Drug Discovery Products

A proton-sensing GPCR is GPR68 (also known as OGR1). Given the dearth of practical pharmaceutical techniques and intrinsic challenges in accounting for the promiscuous activities of protons and dynamic variations in pH, OGR1 and its subfamily members (GPR4, GPR65, and GPR132) have proven to be incredibly challenging to understand and research. GPR68 may be essential for tumor biology, including carcinogenesis, proliferation, and metastasis, according to newly available information.

Creative Biolabs can offer high-quality SPC/LPC/Proton-sensor family in vitro assays and products to meet the needs of our clients:

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Overview of SPC/LPC/Proton-sensor Family

• GPR68

It was initially shown that extracellular acidity activated GPR68, stimulating the Gq/11 protein and increasing IP production. In addition to Gq-coupled signaling, extracellular acidity promotes cyclic AMP (cAMP) buildup when GPR68 is activated. The GPR68/Gs/cAMP pathway was also found in human aortic smooth muscle cells, and it was postulated that GPR68-mediated stimulation of the PLC/COX/PGI2 pathway would result in cAMP buildup. In addition to pH- and GPR68-dependent cAMP buildup in human osteoblastic cells, COX-2-catalyzed PGE2 synthesis also contributes to these effects. Numerous human cancers have been found to contain GPR68 signaling pathways. Through the Gs/cAMP/protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway, GPR68 activation increases IL-6 expression in pancreatic CAFs. In prostate cancer PC3 cells that overexpress GPR68, Gi expression was increased, which led to the release of a migratory inhibitory factor. Cell migration was reduced in MCF7 breast cancer cells overexpressing GPR68 via the Rac1 pathway.

Fig.1. Proton-sensitive GPCR-regulated signaling. (Weiß, 2017)

SPC/LPC/Proton-sensor Family in Cancer

Somatic GPR68 mutations are incredibly uncommon in human malignancies. Numerous human tumors, including MCC, DFSP, AFX, GIST, and appendiceal tumor CAFs, as well as colon cancer CAFs, express the GPR68 gene. Numerous immune cell types, particularly macrophages and T cells, express GPR68. These cells could be involved in the expression of GPR68 in solid tumors as they are probably exposed to the acidic TME. Thus, GPR68 signaling may affect the function of immune cells in tumors.

Fig.2. Summary of GPR68 in cancer cells and other cells. (Wiley, 2019)

SPC/LPC/Proton-sensor Family Drug Discovery

GPR68 sensing of H⁺ is assumed to occur through protonation of histidine residues, which results in conformational changes and receptor activation, in contrast to the ligand-receptor binding pocket interaction of other GPCRs. GPR68's difficulties as a membrane protein, conformational variability in solutions, and the comparatively tiny structured polar surface available for crystal lattice interactions are all contributing factors.

References

1. Weiß, K.T.; et al. Proton‐sensing G protein‐coupled receptors as regulators of cell proliferation and migration during tumor growth and wound healing. Experimental Dermatology. 2017, 26(2): 127-132.
2. Wiley, S.Z.; et al. GPR68: an emerging drug target in cancer. International journal of molecular sciences. 2019, 20(3): 559.