GPR126: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''G protein-coupled receptor 126''' also known as '''VIGR''' and '''DREG''' is a [[protein]] encoded by the ''ADGRG6'' [[gene]].<ref name="pmid12565841">{{cite journal | vauthors = Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB | title = There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini | journal = Biochemical and Biophysical Research Communications | volume = 301 | issue = 3 | pages = 725–34 | date = Feb 2003 | pmid = 12565841 | pmc =  | doi = 10.1016/S0006-291X(03)00026-3 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GPR126 G protein-coupled receptor 126| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57211| accessdate = }}</ref><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|date=April 2015|volume=67|issue=2|pages=338–67|pmid=25713288|doi=10.1124/pr.114.009647|pmc=4394687}}</ref> GPR126 is a member of the [[adhesion-GPCRs|adhesion GPCR]] family.<ref name="isbn1-4419-7912-3">{{cite book | vauthors = 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 |vauthors=Langenhan T, Aust G, Hamann 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>
'''G protein-coupled receptor 126''' also known as '''VIGR''' and '''DREG''' is a [[protein]] encoded by the ''ADGRG6'' [[gene]].<ref name="pmid12565841">{{cite journal | vauthors = Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB | title = There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini | journal = Biochemical and Biophysical Research Communications | volume = 301 | issue = 3 | pages = 725–34 | date = February 2003 | pmid = 12565841 | pmc =  | doi = 10.1016/S0006-291X(03)00026-3 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GPR126 G protein-coupled receptor 126| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57211| access-date = }}</ref><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 | pmc = 4394687 | doi = 10.1124/pr.114.009647 }}</ref> GPR126 is a member of the [[adhesion-GPCRs|adhesion GPCR]] family.<ref name="isbn1-4419-7912-3">{{cite book | vauthors = 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 | vauthors = Langenhan T, Aust G, Hamann J | title = Sticky signaling--adhesion class G protein-coupled receptors take the stage | journal = Science Signaling | volume = 6 | issue = 276 | pages = re3 | date = May 2013 | 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 = Mar 2012 | pmid = 22333914 | pmc = 3321182 | doi = 10.1038/emboj.2012.26 }}</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>


GPR126 is all widely expressed on stromal cells.<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 = Apr 2015 | pmid = 25713288 | doi = 10.1124/pr.114.009647 | pmc=4394687}}</ref> The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules.<ref name="Stehlik C 2004">{{cite journal | vauthors = Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J | title = VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells | journal = FEBS Letters | volume = 569 | issue = 1–3 | pages = 149–55 | date = Jul 2004 | pmid = 15225624 | doi = 10.1016/j.febslet.2004.05.038 }}</ref>
GPR126 is all widely expressed on stromal cells.<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 = Apr 2015 | pmid = 25713288 | pmc = 4394687 | doi = 10.1124/pr.114.009647 }}</ref> The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules.<ref name="Stehlik C 2004">{{cite journal | vauthors = Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J | title = VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells | journal = FEBS Letters | volume = 569 | issue = 1-3 | pages = 149–55 | date = July 2004 | pmid = 15225624 | doi = 10.1016/j.febslet.2004.05.038 }}</ref>


== Ligand ==
== Ligand ==
GPR126 was shown to bind collagen IV and laminin-211 promoting cyclic adenosine monophosphate (cAMP) to mediate myelination.<ref>{{cite journal | vauthors = Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS | title = Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126 | journal = Science Signaling | volume = 7 | issue = 338 | pages = ra76 | date = Aug 2014 | pmid = 25118328 | doi = 10.1126/scisignal.2005347 | pmc=4159047}}</ref><ref name="Petersen SC 2014">{{cite journal | vauthors = Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR | title = The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211 | journal = Neuron | volume = 85 | issue = 4 | pages = 755–69 | date = Feb 2015 | pmid = 25695270 | doi = 10.1016/j.neuron.2014.12.057 | pmc=4335265}}</ref>
GPR126 was shown to bind collagen IV and laminin-211 promoting cyclic adenosine monophosphate (cAMP) to mediate myelination.<ref>{{cite journal | vauthors = Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS | title = Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126 | journal = Science Signaling | volume = 7 | issue = 338 | pages = ra76 | date = August 2014 | pmid = 25118328 | pmc = 4159047 | doi = 10.1126/scisignal.2005347 }}</ref><ref name="Petersen SC 2014">{{cite journal | vauthors = Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR | title = The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211 | journal = Neuron | volume = 85 | issue = 4 | pages = 755–69 | date = February 2015 | pmid = 25695270 | pmc = 4335265 | doi = 10.1016/j.neuron.2014.12.057 }}</ref>


== Signaling ==
== Signaling ==
Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells.<ref name="Stehlik C 2004"/> During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells.<ref name="ReferenceA">{{cite journal | vauthors = Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, Ma Y, Liu M | title = GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling | journal = The Journal of Biological Chemistry | volume = 289 | issue = 50 | pages = 34871–85 | date = Dec 2014 | pmid = 25217645 | doi = 10.1074/jbc.M114.571000 | pmc=4263886}}</ref> Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gα<sub>s/i</sub> proteins.<ref>{{cite journal | vauthors = Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR | title = Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation | journal = The Journal of Neuroscience | volume = 33 | issue = 46 | pages = 17976–85 | date = Nov 2013 | pmid = 24227709 | doi = 10.1523/JNEUROSCI.1809-13.2013 | pmc=3828454}}</ref>
Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells.<ref name="Stehlik C 2004"/> During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells.<ref name="ReferenceA">{{cite journal | vauthors = Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, Ma Y, Liu M | title = GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling | journal = The Journal of Biological Chemistry | volume = 289 | issue = 50 | pages = 34871–85 | date = December 2014 | pmid = 25217645 | pmc = 4263886 | doi = 10.1074/jbc.M114.571000 }}</ref> Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gα<sub>s/i</sub> proteins.<ref>{{cite journal | vauthors = Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR | title = Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation | journal = The Journal of Neuroscience | volume = 33 | issue = 46 | pages = 17976–85 | date = November 2013 | pmid = 24227709 | pmc = 3828454 | doi = 10.1523/JNEUROSCI.1809-13.2013 }}</ref>


== Function ==
== Function ==
GPR126 has been identified in genomic regions associated with adult height, more specially trunk height,<ref>{{cite journal | vauthors = Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K | title = Many sequence variants affecting diversity of adult human height | journal = Nature Genetics | volume = 40 | issue = 5 | pages = 609–15 | date = May 2008 | pmid = 18391951 | doi = 10.1038/ng.122 }}</ref><ref>{{cite journal | vauthors = Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN | title = Identification of ten loci associated with height highlights new biological pathways in human growth | journal = Nature Genetics | volume = 40 | issue = 5 | pages = 584–91 | date = May 2008 | pmid = 18391950 | doi = 10.1038/ng.125 | pmc=2687076}}</ref><ref>{{cite journal | vauthors = Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S, Estrada K, Pols HA, Williams FM, McArdle WL, van Meurs JB, Loos RJ, Dermitzakis ET, Ahmadi KR, Hart DJ, Ouwehand WH, Wareham NJ, Barroso I, Sandhu MS, Strachan DP, Livshits G, Spector TD, Uitterlinden AG, Deloukas P | title = Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size | journal = PLoS Genetics | volume = 5 | issue = 4 | pages = e1000445 | date = Apr 2009 | pmid = 19343178 | doi = 10.1371/journal.pgen.1000445 | pmc=2661236}}</ref> pulmonary function<ref>{{cite journal | vauthors = Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O'Connor GT, London SJ | title = Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function | journal = Nature Genetics | volume = 42 | issue = 1 | pages = 45–52 | date = Jan 2010 | pmid = 20010835 | doi = 10.1038/ng.500 | pmc=2832852}}</ref> and adolescent idiopathic scoliosis.<ref>{{cite journal | vauthors = Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Londono D, Gordon D, Herring JA, Watanabe K, Chiba K, Kamatani N, Jiang Q, Hiraki Y, Kubo M, Toyama Y, Tsunoda T, Wise CA, Qiu Y, Shukunami C, Matsumoto M, Ikegawa S | title = Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis | journal = Nature Genetics | volume = 45 | issue = 6 | pages = 676–9 | date = Jun 2013 | pmid = 23666238 | doi = 10.1038/ng.2639 }}</ref> In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons.<ref>{{cite journal | vauthors = Pogoda HM, Sternheim N, Lyons DA, Diamond B, Hawkins TA, Woods IG, Bhatt DH, Franzini-Armstrong C, Dominguez C, Arana N, Jacobs J, Nix R, Fetcho JR, Talbot WS | title = A genetic screen identifies genes essential for development of myelinated axons in zebrafish | journal = Developmental Biology | volume = 298 | issue = 1 | pages = 118–31 | date = Oct 2006 | pmid = 16875686 | doi = 10.1016/j.ydbio.2006.06.021 }}</ref> GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity.<ref>{{cite journal | vauthors = Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS | title = A G protein-coupled receptor is essential for Schwann cells to initiate myelination | journal = Science | volume = 325 | issue = 5946 | pages = 1402–5 | date = Sep 2009 | pmid = 19745155 | doi = 10.1126/science.1173474 | pmc=2856697}}</ref> Mutation of ''gpr126'' in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development.<ref name="Petersen SC 2014"/>
GPR126 has been identified in genomic regions associated with adult height, more specially trunk height,<ref>{{cite journal | vauthors = Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K | display-authors = 6 | title = Many sequence variants affecting diversity of adult human height | journal = Nature Genetics | volume = 40 | issue = 5 | pages = 609–15 | date = May 2008 | pmid = 18391951 | doi = 10.1038/ng.122 }}</ref><ref>{{cite journal | vauthors = Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN | display-authors = 6 | title = Identification of ten loci associated with height highlights new biological pathways in human growth | journal = Nature Genetics | volume = 40 | issue = 5 | pages = 584–91 | date = May 2008 | pmid = 18391950 | pmc = 2687076 | doi = 10.1038/ng.125 }}</ref><ref>{{cite journal | vauthors = Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S, Estrada K, Pols HA, Williams FM, McArdle WL, van Meurs JB, Loos RJ, Dermitzakis ET, Ahmadi KR, Hart DJ, Ouwehand WH, Wareham NJ, Barroso I, Sandhu MS, Strachan DP, Livshits G, Spector TD, Uitterlinden AG, Deloukas P | display-authors = 6 | title = Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size | journal = PLoS Genetics | volume = 5 | issue = 4 | pages = e1000445 | date = April 2009 | pmid = 19343178 | pmc = 2661236 | doi = 10.1371/journal.pgen.1000445 }}</ref> pulmonary function<ref>{{cite journal | vauthors = Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O'Connor GT, London SJ | display-authors = 6 | title = Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function | journal = Nature Genetics | volume = 42 | issue = 1 | pages = 45–52 | date = January 2010 | pmid = 20010835 | pmc = 2832852 | doi = 10.1038/ng.500 }}</ref> and adolescent idiopathic scoliosis.<ref name="ReferenceB">{{cite journal | vauthors = Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Londono D, Gordon D, Herring JA, Watanabe K, Chiba K, Kamatani N, Jiang Q, Hiraki Y, Kubo M, Toyama Y, Tsunoda T, Wise CA, Qiu Y, Shukunami C, Matsumoto M, Ikegawa S | display-authors = 6 | title = Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis | journal = Nature Genetics | volume = 45 | issue = 6 | pages = 676–9 | date = June 2013 | pmid = 23666238 | doi = 10.1038/ng.2639 }}</ref> In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons.<ref>{{cite journal | vauthors = Pogoda HM, Sternheim N, Lyons DA, Diamond B, Hawkins TA, Woods IG, Bhatt DH, Franzini-Armstrong C, Dominguez C, Arana N, Jacobs J, Nix R, Fetcho JR, Talbot WS | display-authors = 6 | title = A genetic screen identifies genes essential for development of myelinated axons in zebrafish | journal = Developmental Biology | volume = 298 | issue = 1 | pages = 118–31 | date = October 2006 | pmid = 16875686 | doi = 10.1016/j.ydbio.2006.06.021 }}</ref> GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity.<ref>{{cite journal | vauthors = Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS | title = A G protein-coupled receptor is essential for Schwann cells to initiate myelination | journal = Science | volume = 325 | issue = 5946 | pages = 1402–5 | date = September 2009 | pmid = 19745155 | pmc = 2856697 | doi = 10.1126/science.1173474 }}</ref> Mutation of ''gpr126'' in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development.<ref name="Petersen SC 2014"/>


Outside of neurons, GPR126 function is required for heart and inner ear development.<ref>{{cite journal | vauthors = Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP | title = The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse | journal = PLOS ONE | volume = 5 | issue = 11 | pages = e14047 | date = 18 November 2010 | pmid = 21124978 | doi = 10.1371/journal.pone.0014047 | pmc=2987804}}</ref><ref>{{cite journal | vauthors = Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB | title = Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 42 | pages = 16898–903 | date = Oct 2013 | pmid = 24082093 | doi = 10.1073/pnas.1304837110 | pmc=3801000}}</ref><ref>{{cite journal | vauthors = Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT | title = Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene | journal = Development | volume = 140 | issue = 21 | pages = 4362–74 | date = Nov 2013 | pmid = 24067352 | doi = 10.1242/dev.098061 | pmc=4007713}}</ref> GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.<ref name="ReferenceA"/>
Outside of neurons, GPR126 function is required for heart and inner ear development.<ref>{{cite journal | vauthors = Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP | title = The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse | journal = PLOS One | volume = 5 | issue = 11 | pages = e14047 | date = November 2010 | pmid = 21124978 | pmc = 2987804 | doi = 10.1371/journal.pone.0014047 }}</ref><ref>{{cite journal | vauthors = Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB | title = Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 42 | pages = 16898–903 | date = October 2013 | pmid = 24082093 | pmc = 3801000 | doi = 10.1073/pnas.1304837110 }}</ref><ref>{{cite journal | vauthors = Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT | title = Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene | journal = Development | volume = 140 | issue = 21 | pages = 4362–74 | date = November 2013 | pmid = 24067352 | pmc = 4007713 | doi = 10.1242/dev.098061 }}</ref> GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.<ref name="ReferenceA"/>
 
==Disease==
Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development,<ref>{{cite journal | vauthors = Karner CM, Long F, Solnica-Krezel L, Monk KR, Gray RS | title = Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice | journal = Human Molecular Genetics | volume = 24 | issue = 15 | pages = 4365–73 | date = August 2015 | pmid = 25954032 | doi = 10.1093/hmg/ddv170 | pmc = 4492399 }}</ref> supporting findings that variants of GPR126 have been associated with adolescent idiopathic [[scoliosis]],<ref name="ReferenceB"/> and Mutations have been shown to be responsible for severe [[arthrogryposis]] multiplex congenita <ref>{{cite journal | vauthors = Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, Alanio E, Buckland M, Arbuckle S, Krivanek M, Maluenda J, Pannell S, Gooding R, Ong RW, Allcock RJ, Carvalho ED, Carvalho MD, Kok F, Talbot WS, Melki J, Laing NG | display-authors = 6 | title = Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita | journal = American Journal of Human Genetics | volume = 96 | issue = 6 | pages = 955–61 | date = June 2015 | pmid = 26004201 | doi = 10.1016/j.ajhg.2015.04.014 | pmc = 4457946 }}</ref>
{{clear}}


== References ==
== References ==
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{{reflist|32em}}


== External links ==
== External links ==
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{{G protein-coupled receptors}}
{{G protein-coupled receptors}}


[[Category:G protein coupled receptors]]
[[Category:G protein-coupled receptors]]

Latest revision as of 18:00, 24 September 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

G protein-coupled receptor 126 also known as VIGR and DREG is a protein encoded by the ADGRG6 gene.[1][2][3] GPR126 is a member of the adhesion GPCR family.[4][5] 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.[6]

GPR126 is all widely expressed on stromal cells.[7] The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules.[8]

Ligand

GPR126 was shown to bind collagen IV and laminin-211 promoting cyclic adenosine monophosphate (cAMP) to mediate myelination.[9][10]

Signaling

Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells.[8] During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells.[11] Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gαs/i proteins.[12]

Function

GPR126 has been identified in genomic regions associated with adult height, more specially trunk height,[13][14][15] pulmonary function[16] and adolescent idiopathic scoliosis.[17] In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons.[18] GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity.[19] Mutation of gpr126 in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development.[10]

Outside of neurons, GPR126 function is required for heart and inner ear development.[20][21][22] GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.[11]

Disease

Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development,[23] supporting findings that variants of GPR126 have been associated with adolescent idiopathic scoliosis,[17] and Mutations have been shown to be responsible for severe arthrogryposis multiplex congenita [24]

References

  1. ↑ Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB (February 2003). "There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini". Biochemical and Biophysical Research Communications. 301 (3): 725–34. doi:10.1016/S0006-291X(03)00026-3. PMID 12565841.
  2. ↑ "Entrez Gene: GPR126 G protein-coupled receptor 126".
  3. ↑ 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.
  4. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 1-4419-7912-3.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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. PMC 4394687. PMID 25713288.
  8. ↑ 8.0 8.1 Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J (July 2004). "VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells". FEBS Letters. 569 (1–3): 149–55. doi:10.1016/j.febslet.2004.05.038. PMID 15225624.
  9. ↑ Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS (August 2014). "Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126". Science Signaling. 7 (338): ra76. doi:10.1126/scisignal.2005347. PMC 4159047. PMID 25118328.
  10. ↑ 10.0 10.1 Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR (February 2015). "The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211". Neuron. 85 (4): 755–69. doi:10.1016/j.neuron.2014.12.057. PMC 4335265. PMID 25695270.
  11. ↑ 11.0 11.1 Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, Ma Y, Liu M (December 2014). "GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling". The Journal of Biological Chemistry. 289 (50): 34871–85. doi:10.1074/jbc.M114.571000. PMC 4263886. PMID 25217645.
  12. ↑ Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR (November 2013). "Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation". The Journal of Neuroscience. 33 (46): 17976–85. doi:10.1523/JNEUROSCI.1809-13.2013. PMC 3828454. PMID 24227709.
  13. ↑ Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, et al. (May 2008). "Many sequence variants affecting diversity of adult human height". Nature Genetics. 40 (5): 609–15. doi:10.1038/ng.122. PMID 18391951.
  14. ↑ Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, et al. (May 2008). "Identification of ten loci associated with height highlights new biological pathways in human growth". Nature Genetics. 40 (5): 584–91. doi:10.1038/ng.125. PMC 2687076. PMID 18391950.
  15. ↑ Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, et al. (April 2009). "Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size". PLoS Genetics. 5 (4): e1000445. doi:10.1371/journal.pgen.1000445. PMC 2661236. PMID 19343178.
  16. ↑ Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. (January 2010). "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function". Nature Genetics. 42 (1): 45–52. doi:10.1038/ng.500. PMC 2832852. PMID 20010835.
  17. ↑ 17.0 17.1 Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. (June 2013). "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis". Nature Genetics. 45 (6): 676–9. doi:10.1038/ng.2639. PMID 23666238.
  18. ↑ Pogoda HM, Sternheim N, Lyons DA, Diamond B, Hawkins TA, Woods IG, et al. (October 2006). "A genetic screen identifies genes essential for development of myelinated axons in zebrafish". Developmental Biology. 298 (1): 118–31. doi:10.1016/j.ydbio.2006.06.021. PMID 16875686.
  19. ↑ Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS (September 2009). "A G protein-coupled receptor is essential for Schwann cells to initiate myelination". Science. 325 (5946): 1402–5. doi:10.1126/science.1173474. PMC 2856697. PMID 19745155.
  20. ↑ Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP (November 2010). "The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse". PLOS One. 5 (11): e14047. doi:10.1371/journal.pone.0014047. PMC 2987804. PMID 21124978.
  21. ↑ Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB (October 2013). "Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent". Proceedings of the National Academy of Sciences of the United States of America. 110 (42): 16898–903. doi:10.1073/pnas.1304837110. PMC 3801000. PMID 24082093.
  22. ↑ Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT (November 2013). "Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene". Development. 140 (21): 4362–74. doi:10.1242/dev.098061. PMC 4007713. PMID 24067352.
  23. ↑ Karner CM, Long F, Solnica-Krezel L, Monk KR, Gray RS (August 2015). "Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice". Human Molecular Genetics. 24 (15): 4365–73. doi:10.1093/hmg/ddv170. PMC 4492399. PMID 25954032.
  24. ↑ Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, et al. (June 2015). "Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita". American Journal of Human Genetics. 96 (6): 955–61. doi:10.1016/j.ajhg.2015.04.014. PMC 4457946. PMID 26004201.

External links

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