View source for GPR64

{{Infobox gene}}
'''G protein-coupled receptor 64''' also known as '''HE6''' is a [[protein]] encoded by the ''ADGRG2'' [[gene]].<ref>{{cite journal|last1=Hamann|first1=J|last2=Aust|first2=G|last3=Araç|first3=D|last4=Engel|first4=FB|last5=Formstone|first5=C|last6=Fredriksson|first6=R|last7=Hall|first7=RA|last8=Harty|first8=BL|last9=Kirchhoff|first9=C|last10=Knapp|first10=B|last11=Krishnan|first11=A|last12=Liebscher|first12=I|last13=Lin|first13=HH|last14=Martinelli|first14=DC|last15=Monk|first15=KR|last16=Peeters|first16=MC|last17=Piao|first17=X|last18=Prömel|first18=S|last19=Schöneberg|first19=T|last20=Schwartz|first20=TW|last21=Singer|first21=K|last22=Stacey|first22=M|last23=Ushkaryov|first23=YA|last24=Vallon|first24=M|last25=Wolfrum|first25=U|last26=Wright|first26=MW|last27=Xu|first27=L|last28=Langenhan|first28=T|last29=Schiöth|first29=HB|title=International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.|journal=Pharmacological Reviews|date=April 2015|volume=67|issue=2|pages=338–67|pmid=25713288|doi=10.1124/pr.114.009647|pmc=4394687}}</ref> GPR64 is a member of the [[adhesion-GPCRs|adhesion GPCR]] family.<ref name="isbn1-4419-7912-3">{{cite book | author = Stacey M, Yona S | title = Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology) | publisher = Springer | location = Berlin | year = 2011 | pages = | isbn = 1-4419-7912-3 }}</ref><ref>{{cite journal|last1=Langenhan|first1=T|last2=Aust|first2=G|last3=Hamann|first3=J|title=Sticky signaling--adhesion class G protein-coupled receptors take the stage.|journal=Science signaling|date=21 May 2013|volume=6|issue=276|pages=re3|pmid=23695165|doi=10.1126/scisignal.2003825}}</ref>
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|(GAIN)]] domain.<ref name="pmid22333914">{{cite journal | vauthors = Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT | title = A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis | journal = The EMBO Journal | volume = 31 | issue = 6 | pages = 1364–78 | date = March 2012 | pmid = 22333914 | pmc = 3321182 | doi = 10.1038/emboj.2012.26 }}</ref>

The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated.<ref>{{cite journal | vauthors = Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U | year = 2004 | title = Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility | journal = Mol Cell Biol | volume = 24 | issue = | pages = 8642–8648 | doi=10.1128/mcb.24.19.8642-8648.2004 | pmid=15367682 | pmc=516748}}</ref>  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.<ref>{{cite journal | vauthors = Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, Schiöth HB, Fredriksson R | year = 2008 | title = Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat | url = | journal = BMC Neurosci | volume = 9 | issue = 1| pages = 43–43 | doi = 10.1186/1471-2202-9-43 }}</ref> GPR64 is mainly expressed in human and mouse epididymis as well as human prostate and parathyroid.<ref>{{cite journal | vauthors = 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 | title = International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors | journal = Pharmacological Reviews | volume = 67 | issue = 2 | pages = 338–67 | date = April 2015 | pmid = 25713288 | doi = 10.1124/pr.114.009647 | pmc=4394687}}</ref> 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.<ref>{{cite journal | vauthors = Obermann H, Samalecos A, Osterhoff C, Schröder B, Heller R, Kirchhoff C | title = HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia | journal = Molecular Reproduction and Development | volume = 64 | issue = 1 | pages = 13–26 | date = Jan 2003 | pmid = 12420295 | doi = 10.1002/mrd.10220 }}</ref><ref>{{cite journal | vauthors = Kirchhoff C, Osterhoff C, Samalecos A | title = HE6/GPR64 adhesion receptor co-localizes with apical and subapical F-actin scaffold in male excurrent duct epithelia | journal = Reproduction | volume = 136 | issue = 2 | pages = 235–45 | date = August 2008 | pmid = 18469038 | doi = 10.1530/REP-08-0078 }}</ref>

== Function ==
Targeting of ''Gpr64'' in mice causes reduced fertility or infertility in males; but the reproductive capacity was unaffected in females.<ref>{{cite journal | vauthors = Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U | title = Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility | journal = Molecular and Cellular Biology | volume = 24 | issue = 19 | pages = 8642–8 | date = October 2004 | pmid = 15367682 | doi = 10.1128/MCB.24.19.8642-8648.2004 | pmc=516748}}</ref> 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.<ref>{{cite journal | vauthors = Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN | title = Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity | journal = Genes and Immunity | volume = 8 | issue = 6 | pages = 480–91 | date = September 2007 | pmid = 17568789 | doi = 10.1038/sj.gene.6364400 }}</ref>

== Clinical significance ==
GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma,<ref>{{cite journal | vauthors = Whittier KL, Boese EA, Gibson-Corley KN, Kirby PA, Darbro BW, Qian Q, Ingram WJ, Robertson T, Remke M, Taylor MD, O'Dorisio MS | title = G-protein coupled receptor expression patterns delineate medulloblastoma subgroups | journal = Acta Neuropathologica Communications | volume = 1 | issue = 1 | pages = 66 | date = 10 October 2013 | pmid = 24252460 | doi = 10.1186/2051-5960-1-66 | pmc=3893540}}</ref> as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung.<ref name="ReferenceA">{{cite journal | vauthors = Richter GH, Fasan A, Hauer K, Grunewald TG, Berns C, Rössler S, Naumann I, Staege MS, Fulda S, Esposito I, Burdach S | title = G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1 | journal = The Journal of Pathology | volume = 230 | issue = 1 | pages = 70–81 | date = May 2013 | pmid = 23338946 | doi = 10.1002/path.4170 }}</ref> Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1.<ref name="ReferenceA"/>

== References ==
{{reflist|33em}}

== External links ==
* [http://www.adhesiongpcr.org/ Adhesion GPCR consortium]
* {{UCSC genome browser|GPR64}}

{{G protein-coupled receptors}}
{{Use dmy dates|date=April 2017}}

[[Category:G protein coupled receptors]]