Wikipedia

GPR64

G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene.[5] GPR64 is a member of the adhesion GPCR family.[6][7] 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.[8][9]

ADGRG2
Identifiers
AliasesADGRG2, EDDM6, HE6, TM7LN2, GPR64, adhesion G protein-coupled receptor G2, CBAVDX
External IDsOMIM: 300572; MGI: 2446854; HomoloGene: 4208; GeneCards: ADGRG2; OMA:ADGRG2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10149

237175

Ensembl

ENSG00000173698

ENSMUSG00000031298

UniProt

Q8IZP9

Q8CJ12

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr X: 18.99 – 19.12 MbChr X: 159.17 – 159.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated.[10] 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[11] and central nervous system.[12] GPR64 is mainly expressed in human and mouse epididymis as well as human prostate and parathyroid.[11][13] 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.[14][15]

Function

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Targeting of Gpr64 in mice causes reduced fertility or infertility in males; but the reproductive capacity was unaffected in females.[16] 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.[17]

Clinical significance

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GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma,[18] as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung.[19] Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1.[19] Upregulation and activation of GPR64 are associated with primary hyperparathyroidism and hypersecretion of parathyroid hormone.[11]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000173698 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031298 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, et al. (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–367. doi:10.1124/pr.114.009647. PMC 4394687. PMID 25713288.
  6. ^ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 978-1-4419-7912-4.
  7. ^ Langenhan T, Aust G, Hamann J (May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling. 6 (276): re3. doi:10.1126/scisignal.2003825. PMID 23695165. S2CID 6958640.
  8. ^ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, et al. (March 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal. 31 (6): 1364–1378. doi:10.1038/emboj.2012.26. PMC 3321182. PMID 22333914.
  9. ^ Azimzadeh P, Talamantez-Lyburn SC, Chang KT, Inoue A, Balenga N (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. Bibcode:2019NYASA1456...26A. doi:10.1111/nyas.14227. PMC 7236788. PMID 31502283.
  10. ^ Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, et al. (October 2004). "Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility". Molecular and Cellular Biology. 24 (19): 8642–8648. doi:10.1128/mcb.24.19.8642-8648.2004. PMC 516748. PMID 15367682.
  11. ^ a b c Balenga N, Azimzadeh P, Hogue JA, Staats PN, Shi Y, Koh J, et al. (March 2017). "Orphan Adhesion GPCR GPR64/ADGRG2 Is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling". Journal of Bone and Mineral Research. 32 (3): 654–666. doi:10.1002/jbmr.3023. PMC 7211037. PMID 27760455.
  12. ^ Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, et al. (April 2008). "Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat". BMC Neuroscience. 9 (1): 43. doi:10.1186/1471-2202-9-43. PMC 2386866. PMID 18445277.
  13. ^ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, et al. (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–367. doi:10.1124/pr.114.009647. PMC 4394687. PMID 25713288.
  14. ^ Obermann H, Samalecos A, Osterhoff C, Schröder B, Heller R, Kirchhoff C (January 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. S2CID 29953802.
  15. ^ 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): 235–245. doi:10.1530/REP-08-0078. PMID 18469038.
  16. ^ Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, et al. (October 2004). "Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility". Molecular and Cellular Biology. 24 (19): 8642–8648. doi:10.1128/MCB.24.19.8642-8648.2004. PMC 516748. PMID 15367682.
  17. ^ 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): 480–491. doi:10.1038/sj.gene.6364400. PMID 17568789. S2CID 22240185.
  18. ^ Whittier KL, Boese EA, Gibson-Corley KN, Kirby PA, Darbro BW, Qian Q, et al. (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.
  19. ^ a b Richter GH, Fasan A, Hauer K, Grunewald TG, Berns C, Rössler S, et al. (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. S2CID 11129426.
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