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 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.
^Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN1-4419-7912-3.
^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.
^Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility" Mol Cell Biol 2004; 24: 8642 8648
^Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, Schiöth HB, Fredriksson R. Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci. 2008;9:43–43. doi:10.1186/1471-2202-9-43
^Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (Apr 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–67. doi:10.1124/pr.114.009647. PMID25713288.
^Obermann H, Samalecos A, Osterhoff C, Schröder B, Heller R, Kirchhoff C (Jan 2003). "HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia". Molecular Reproduction and Development. 64 (1): 13–26. doi:10.1002/mrd.10220. PMID12420295.
^Kirchhoff C, Osterhoff C, Samalecos A (Aug 2008). "HE6/GPR64 adhesion receptor co-localizes with apical and subapical F-actin scaffold in male excurrent duct epithelia". Reproduction. 136 (2): 235–45. doi:10.1530/REP-08-0078. PMID18469038.
^Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U (Oct 2004). "Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility". Molecular and Cellular Biology. 24 (19): 8642–8. doi:10.1128/MCB.24.19.8642-8648.2004. PMID15367682.
^Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN (Sep 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.
^Whittier KL, Boese EA, Gibson-Corley KN, Kirby PA, Darbro BW, Qian Q, Ingram WJ, Robertson T, Remke M, Taylor MD, O'Dorisio MS (10 October 2013). "G-protein coupled receptor expression patterns delineate medulloblastoma subgroups". Acta Neuropathologica Communications. 1 (1): 66. doi:10.1186/2051-5960-1-66. PMID24252460.
^ 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.