G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2gene. GPR64 is a member of the adhesion GPCR family.
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated. GPR64's N-terminus has been reported to be cleaved at the GPS domain to allow for trafficking to the plasma membrane. After cleavage the N-terminus is believed to remain non-covalently associated with the 7TM. GPR64 expression has been mostly reported in the male reproductive organs, but more recently has been shown to be expressed in the parathyroid glands and central nervous system. GPR64 is mainly expressed in human and mouse epididymis as well as human prostate and parathyroid. GPR64, together with F-actin scaffold, locates at the nonciliated principal cells of the proximal male excurrent duct epithelia, where reabsorption of testicular fluid and concentration of sperm takes place.
Targeting of Gpr64 in mice causes reduced fertility or infertility in males; but the reproductive capacity was unaffected in females. Unchanged hormone expression in knockout males indicates that the receptor functions immediately in the male genital tract. Lack of Gpr64 expression causes sperm stasis and duct obstruction due to abnormal fluid reabsorption. In addition, expression of GPR64 has been found in fibroblast-like synovial cells obtained from osteoarthritis but not from rheumatoid arthritis.
GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma, as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung. Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1. Upregulation and activation of GPR64 are associated with primary hyperparathyroidism and hypersecretion of parathyroid hormone.
^Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN978-1-4419-7912-4.
^Langenhan, T; Aust, G; Hamann, J (21 May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling. 6 (276): re3. doi:10.1126/scisignal.2003825. PMID23695165.
^Azimzadeh, Pedram; Talamantez-Lyburn, Sarah C.; Chang, Katarina T.; Inoue, Asuka; Balenga, Nariman (November 2019). "Spatial regulation of GPR64/ADGRG2 signaling by β-arrestins and GPCR kinases". Annals of the New York Academy of Sciences. 1456 (1): 26–43. doi:10.1111/nyas.14227. ISSN1749-6632. PMID31502283.
^Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN (September 2007). "Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity". Genes and Immunity. 8 (6): 480–91. doi:10.1038/sj.gene.6364400. PMID17568789.
^ abRichter GH, Fasan A, Hauer K, Grunewald TG, Berns C, Rössler S, Naumann I, Staege MS, Fulda S, Esposito I, Burdach S (May 2013). "G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1". The Journal of Pathology. 230 (1): 70–81. doi:10.1002/path.4170. PMID23338946.