GRK6

{{Short description|Protein-coding gene in the species Homo sapiens}}

This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5.{{cite journal |vauthors=Benovic JL, Gomez J |title=Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family |journal=J Biol Chem |volume=268 |issue=26 |pages=19521–19527 |year=1993 |doi=10.1016/S0021-9258(19)36546-9 |pmid=8366096 |doi-access=free }}{{cite journal |vauthors=Haribabu B, Snyderman R |title=Identification of additional members of human G-protein-coupled receptor kinase multigene family |journal=Proc Natl Acad Sci USA |volume=90 |issue=20 |pages=9398–9402 |year=1993 |pmid=8415712 |doi=10.1073/pnas.90.20.9398 |pmc=47575 |bibcode=1993PNAS...90.9398H |doi-access=free }}{{cite journal |vauthors=Premont RT, Inglese J, Lefkowitz RJ |title=Protein kinases that phosphorylate activated G protein-coupled receptors |journal=FASEB J |volume=9 |issue=2 |pages=175–182 |year=1995 |pmid=7781920 |doi=10.1096/fasebj.9.2.7781920 |doi-access=free |s2cid=20428064 }} The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

Function

G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.{{cite journal |vauthors=Gurevich VV, Gurevich EV |title=GPCR Signaling Regulation: The Role of GRKs and Arrestins |journal=Front Pharmacol |volume=10 |year=2019 |page=125 |pmid=30837883 |doi=10.3389/fphar.2019.00125 |pmc=6389790 |doi-access=free }}

GRK6 and the closely related GRK5 phosphorylate receptors at sites that encourage arrestin-mediated signaling rather than arrestin-mediated receptor desensitization, internalization and trafficking (in contrast to GRK2 and GRK3, which have the opposite effect).{{cite journal |vauthors=Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ |title=Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling |journal=Proc Natl Acad Sci USA |volume=102 |issue=5 |pages=1442–1447 |year=2005 |pmid=15671181 |doi=10.1073/pnas.0409532102 |pmc=547874 |bibcode=2005PNAS..102.1442K |doi-access=free }}{{cite journal |vauthors=Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ |title=Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor |journal=Proc Natl Acad Sci USA |volume=102 |issue=5 |pages=1448–1453 |year=2005 |pmid=15671180 |doi=10.1073/pnas.0409534102 |pmc=547876 |bibcode=2005PNAS..102.1448R |doi-access=free }} This difference is one basis for pharmacological biased agonism (also called functional selectivity), where a drug binding to a receptor may bias that receptor's signaling toward a particular subset of the actions stimulated by that receptor.{{cite journal |vauthors=Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ |title=Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands |journal=Proc Natl Acad Sci USA |volume=106 |issue=24 |pages=9649–9654 |year=2009 |pmid=19497875 |doi=10.1073/pnas.0904361106 |pmc=2689814|bibcode=2009PNAS..106.9649Z |doi-access=free }}{{cite journal |vauthors=Choi M, Staus DP, Wingler LM, Ahn S, Pani B, Capel WD, Lefkowitz RJ |title=G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor |journal=Sci Signal |volume=11 |issue=544 |page= eaar7084|year=2018 |pmid=30131371 |doi=10.1126/scisignal.aar7084 |doi-access=free }}

GRK6 is widely and relatively evenly expressed throughout the body, but with particularly high expression in immune cells. GRK6 exists in three splice variants that differ in the carboxyl terminal region that regulates membrane association: one form is palmitoylated, another contains a lipid-binding polybasic domain, and the third is truncated and has neither.{{cite journal |vauthors= Premont RT, Macrae AD, Aparicio SA, Kendall HE, Welch JE, Lefkowitz RJ |title= The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation |journal= J Biol Chem |volume=274 |issue=41 |pages=29381–29389 |year=1999 |pmid=10506199 |doi=10.1074/jbc.274.41.29381 |doi-access=free }} In the mouse, GRK6 regulates the D2 dopamine receptor in the striatum region of the brain, and loss of GRK6 leads to increased sensitivity to psychostimulant drugs that act through dopamine.{{cite journal |vauthors=Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT |title=Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice |journal=Neuron |volume=38 |issue=2 |pages=291–303 |year=2003 |pmid=12718862 |doi=10.1016/S0896-6273(03)00192-2 |s2cid=13986538 |doi-access=free }} Overexpression of GRK6 in the striatum in a rat model of Parkinson's disease improves drug-induced movement disorder (tardive dyskinesia) symptoms arising from L-DOPA therapy.{{cite journal |vauthors=Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E |title=Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease |journal= Sci Transl Med |volume=2 |issue=28 |pages=28ra28 |year=2010 |pmid=20410529 |doi=10.1126/scitranslmed.3000664 |pmc=2933751 }} In mouse immune cells, GRK6 is important for chemotaxis of B-lymphocytes and T-lymphocytes in response to the chemoattractant CXCL12,{{cite journal |vauthors=Fong AM, Premont RT, Richardson RM, Yu YR, Lefkowitz RJ, Patel DD |title=Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice |journal=Proc Natl Acad Sci USA |volume=99 |issue=11 |pages=7478–7483 |year=2002 |pmid=12032308 |doi= 10.1073/pnas.112198299 |pmc=124256|bibcode=2002PNAS...99.7478F |doi-access=free }} and of neutrophils to sites of injury in response to leukotriene B4.{{cite journal |vauthors=Kavelaars A, Vroon A, Raatgever RP, Fong AM, Premont RT, Patel DD, Lefkowitz RJ, Heijnen CJ |title=Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6 |journal=J Immunol |volume=171 |issue=11 |pages=6128–6134 |year=2003 |pmid=14634128 |doi=10.4049/jimmunol.171.11.6128 |doi-access=free }}

References

{{cite journal | author=Bullrich F |title=Chromosomal mapping of the genes GPRK5 and GPRK6 encoding G protein-coupled receptor kinases GRK5 and GRK6 |journal=Cytogenet. Cell Genet. |volume=70 |issue= 3–4 |pages= 250–4 |year= 1995 |pmid= 7789183 |doi=10.1159/000134045 |name-list-style=vanc| author2=Druck T | author3=Kunapuli P | display-authors=3 | last4=Gomez | first4=J. | last5=Gripp | first5=K.W. | last6=Schlegelberger | first6=B. | last7=Lasota | first7=J. | last8=Aronson | first8=M. | last9=Cannizzaro | first9=L.A. }}
{{cite journal | author=Stoffel RH |title=Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family |journal=J. Biol. Chem. |volume=269 |issue= 45 |pages= 27791–4 |year= 1994 |pmid= 7961702 |name-list-style=vanc| author2=Randall RR | author3=Premont RT | display-authors=3 | last4=Lefkowitz | first4=RJ | last5=Inglese | first5=J |doi=10.1016/S0021-9258(18)46852-4 |doi-access=free }}
{{cite journal |vauthors=Loudon RP, Benovic JL |title=Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6 |journal=J. Biol. Chem. |volume=269 |issue= 36 |pages= 22691–7 |year= 1994 |doi=10.1016/S0021-9258(17)31701-5 |pmid= 8077221 |doi-access=free }}
{{cite journal |vauthors=Benovic JL, Gomez J |title=Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family |journal=J. Biol. Chem. |volume=268 |issue= 26 |pages= 19521–7 |year= 1993 |doi=10.1016/S0021-9258(19)36546-9 |pmid= 8366096 |doi-access=free }}
{{cite journal | author=Freedman NJ |title=Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity |journal=J. Biol. Chem. |volume=272 |issue= 28 |pages= 17734–43 |year= 1997 |pmid= 9211925 |doi=10.1074/jbc.272.28.17734 |name-list-style=vanc| author2=Ament AS | author3=Oppermann M | display-authors=3 | last4=Stoffel | first4=RH | last5=Exum | first5=ST | last6=Lefkowitz | first6=RJ | doi-access=free }}
{{cite journal |vauthors=Loudon RP, Benovic JL |title=Altered activity of palmitoylation-deficient and isoprenylated forms of the G protein-coupled receptor kinase GRK6 |journal=J. Biol. Chem. |volume=272 |issue= 43 |pages= 27422–7 |year= 1997 |pmid= 9341194 |doi=10.1074/jbc.272.43.27422 |doi-access=free }}
{{cite journal | author=Stoffel RH |title=Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6 |journal=Biochemistry |volume=37 |issue= 46 |pages= 16053–9 |year= 1998 |pmid= 9819198 |doi= 10.1021/bi981432d |name-list-style=vanc| author2=Inglese J | author3=Macrae AD | display-authors=3 | last4=Lefkowitz | first4=Robert J. | last5=Premont | first5=Richard T. |s2cid=26096361 }}
{{cite journal | author=Premont RT |title=β2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 24 |pages= 14082–7 |year= 1998 |pmid= 9826657 |doi=10.1073/pnas.95.24.14082 | pmc=24330 |name-list-style=vanc| author2=Claing A | author3=Vitale N | display-authors=3 | last4=Freeman | first4=JL | last5=Pitcher | first5=JA | last6=Patton | first6=WA | last7=Moss | first7=J | last8=Vaughan | first8=M | last9=Lefkowitz | first9=RJ |bibcode=1998PNAS...9514082P |doi-access=free }}
{{cite journal | author=Milcent MD |title=Overexpression of wild-type and catalytically inactive forms of GRK2 and GRK6 fails to alter the agonist-induced phosphorylation of the C5a receptor (CD88): evidence that GRK6 is autophosphorylated in COS-7 cells |journal=Biochem. Biophys. Res. Commun. |volume=259 |issue= 1 |pages= 224–9 |year= 1999 |pmid= 10334944 |doi= 10.1006/bbrc.1999.0758 |name-list-style=vanc| author2=Christophe T | author3=Rabiet MJ | display-authors=3 | last4=Tardif | first4=Marianne | last5=Boulay | first5=François }}
{{cite journal | author=Lazari MF |title=Role of G protein-coupled receptor kinases on the agonist-induced phosphorylation and internalization of the follitropin receptor |journal=Mol. Endocrinol. |volume=13 |issue= 6 |pages= 866–78 |year= 1999 |pmid= 10379886 |doi=10.1210/me.13.6.866 |name-list-style=vanc| author2=Liu X | author3=Nakamura K | display-authors=3 | last4=Benovic | first4=JL | last5=Ascoli | first5=M |doi-access=free}}
{{cite journal | author=Hall RA |title=G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction |journal=J. Biol. Chem. |volume=274 |issue= 34 |pages= 24328–34 |year= 1999 |pmid= 10446210 |doi=10.1074/jbc.274.34.24328 |name-list-style=vanc| author2=Spurney RF | author3=Premont RT | display-authors=3 | last4=Rahman | first4=N | last5=Blitzer | first5=JT | last6=Pitcher | first6=JA | last7=Lefkowitz | first7=RJ | doi-access=free }}
{{cite journal |vauthors=Brenninkmeijer CB, Price SA, López Bernal A, Phaneuf S |title=Expression of G-protein-coupled receptor kinases in pregnant term and non-pregnant human myometrium |journal=J. Endocrinol. |volume=162 |issue= 3 |pages= 401–8 |year= 1999 |pmid= 10467231 |doi=10.1677/joe.0.1620401 |doi-access=free }}
{{cite journal |vauthors=Pronin AN, Morris AJ, Surguchov A, Benovic JL |title=Synucleins are a novel class of substrates for G protein-coupled receptor kinases |journal=J. Biol. Chem. |volume=275 |issue= 34 |pages= 26515–22 |year= 2000 |pmid= 10852916 |doi= 10.1074/jbc.M003542200 |doi-access= free }}
{{cite journal | author=Tiruppathi C |title=G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 13 |pages= 7440–5 |year= 2000 |pmid= 10861009 |doi=10.1073/pnas.97.13.7440 | pmc=16564 |name-list-style=vanc| author2=Yan W | author3=Sandoval R | display-authors=3 | last4=Naqvi | first4=T | last5=Pronin | first5=AN | last6=Benovic | first6=JL | last7=Malik | first7=AB |bibcode=2000PNAS...97.7440T |doi-access=free }}
{{cite journal |vauthors=Zhou H, Yan F, Tai HH |title=Phosphorylation and desensitization of the human thromboxane receptor-alpha by G protein-coupled receptor kinases |journal=J. Pharmacol. Exp. Ther. |volume=298 |issue= 3 |pages= 1243–51 |year= 2001 |pmid= 11504827 }}
{{cite journal | author=Blaukat A |title=Determination of bradykinin B2 receptor in vivo phosphorylation sites and their role in receptor function |journal=J. Biol. Chem. |volume=276 |issue= 44 |pages= 40431–40 |year= 2001 |pmid= 11517230 |doi= 10.1074/jbc.M107024200 |name-list-style=vanc| author2=Pizard A | author3=Breit A | display-authors=3 | last4=Wernstedt | first4=C | last5=Alhenc-Gelas | first5=F | last6=Muller-Esterl | first6=W | last7=Dikic | first7=I | doi-access=free }}
{{cite journal |vauthors=Willets JM, Challiss RA, Nahorski SR |title=Endogenous G protein-coupled receptor kinase 6 Regulates M3 muscarinic acetylcholine receptor phosphorylation and desensitization in human SH-SY5Y neuroblastoma cells |journal=J. Biol. Chem. |volume=277 |issue= 18 |pages= 15523–9 |year= 2002 |pmid= 11856737 |doi= 10.1074/jbc.M111217200 |doi-access= free }}
{{cite journal | author=Grange-Midroit M |title=G protein-coupled receptor kinases, beta-arrestin-2 and associated regulatory proteins in the human brain: postmortem changes, effect of age and subcellular distribution |journal=Brain Res. Mol. Brain Res. |volume=101 |issue= 1–2 |pages= 39–51 |year= 2002 |pmid= 12007830 |doi=10.1016/S0169-328X(02)00144-4 |name-list-style=vanc| author2=García-Sevilla JA | author3=Ferrer-Alcón M | display-authors=3 | last4=La Harpe | first4=R | last5=Walzer | first5=C | last6=Guimón | first6=J }}

Category:EC 2.7.11

GRK6

Function

References

Further reading