G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene. 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.
- 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 (April 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. PMC 4394687. PMID 25713288.
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- Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (March 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal. 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC 3321182. PMID 22333914.
- Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U (2004). "Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility". Mol Cell Biol. 24 (19): 8642–8648. doi:10.1128/mcb.24.19.8642-8648.2004. PMC 516748. PMID 15367682.
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- 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. PMID 12420295.
- Kirchhoff C, Osterhoff C, Samalecos A (August 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. PMID 18469038.
- Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U (October 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. PMC 516748. PMID 15367682.
- 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. PMID 17568789.
- 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. PMC 3893540. PMID 24252460.
- Richter 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. PMID 23338946.