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F r o m W i k i p e d i a , t h e f r e e e n c y c l o p e d i a
Protein-coding gene in the species Homo sapiens
GRK6 , GPRK6, G protein-coupled receptor kinase 6
OMIM : 600869 ; MGI : 1347078 ; HomoloGene : 37570 ; GeneCards : GRK6 ; OMA :GRK6 - orthologs
Chromosome 5 (human) [1]
5q35.3
Start
177,403,204 bp [1]
177,442,901 bp [1]
Chromosome 13 (mouse)[2]
13 B1|13 30.06 cM
Start
55,592,885 bp [2]
55,608,740 bp [2]
beta cell
pancreatic ductal cell
male germ cell
fossa
external carotid artery
granulocyte
Rostral migratory stream
blood
spleen
protein binding
ATP binding
G protein-coupled receptor kinase activity
kinase activity
beta-adrenergic receptor kinase activity
phosphorylation
regulation of G protein-coupled receptor signaling pathway
signal transduction
G protein-coupled receptor signaling pathway
Chr 5: 177.4 – 177.44 Mb
Chr 13: 55.59 – 55.61 Mb
[3]
[4]
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 .[5] [6] [7] The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling .
Function [ edit ]
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.[8]
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).[9] [10] 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.[11] [12]
GRK6 is widely and relatively evenly expressed throughout the body, but with particularly high expression in immune cells.[6] 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.[13] 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.[14] 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.[15] In mouse immune cells, GRK6 is important for chemotaxis of B-lymphocytes and T-lymphocytes in response to the chemoattractant CXCL12 ,[16] and of neutrophils to sites of injury in response to leukotriene B4 .[17]
References [ edit ]
^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ Benovic JL, Gomez J (1993). "Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family" . J Biol Chem . 268 (26 ): 19521–19527. doi :10.1016/S0021-9258(19 )36546-9 . PMID 8366096 .
^ a b Haribabu B, Snyderman R (1993). "Identification of additional members of human G-protein-coupled receptor kinase multigene family" . Proc Natl Acad Sci USA . 90 (20 ): 9398–9402. Bibcode :1993PNAS...90.9398H . doi :10.1073/pnas.90.20.9398 . PMC 47575 . PMID 8415712 .
^ Premont RT, Inglese J, Lefkowitz RJ (1995). "Protein kinases that phosphorylate activated G protein-coupled receptors" . FASEB J . 9 (2 ): 175–182. doi :10.1096/fasebj.9.2.7781920 . PMID 7781920 . S2CID 20428064 .
^ Gurevich VV, Gurevich EV (2019). "GPCR Signaling Regulation: The Role of GRKs and Arrestins" . Front Pharmacol . 10 : 125. doi :10.3389/fphar.2019.00125 . PMC 6389790 . PMID 30837883 .
^ Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ (2005). "Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling" . Proc Natl Acad Sci USA . 102 (5 ): 1442–1447. Bibcode :2005PNAS..102.1442K . doi :10.1073/pnas.0409532102 . PMC 547874 . PMID 15671181 .
^ Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ (2005). "Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor" . Proc Natl Acad Sci USA . 102 (5 ): 1448–1453. Bibcode :2005PNAS..102.1448R . doi :10.1073/pnas.0409534102 . PMC 547876 . PMID 15671180 .
^ Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ (2009). "Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands" . Proc Natl Acad Sci USA . 106 (24 ): 9649–9654. Bibcode :2009PNAS..106.9649Z . doi :10.1073/pnas.0904361106 . PMC 2689814 . PMID 19497875 .
^ Choi M, Staus DP, Wingler LM, Ahn S, Pani B, Capel WD, Lefkowitz RJ (2018). "G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor" . Sci Signal . 11 (544): eaar7084. doi :10.1126/scisignal.aar7084 . PMID 30131371 .
^ Premont RT, Macrae AD, Aparicio SA, Kendall HE, Welch JE, Lefkowitz RJ (1999). "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation" . J Biol Chem . 274 (41 ): 29381–29389. doi :10.1074/jbc.274.41.29381 . PMID 10506199 .
^ Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT (2003). "Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice" . Neuron . 38 (2 ): 291–303. doi :10.1016/S0896-6273(03 )00192-2 . PMID 12718862 . S2CID 13986538 .
^ 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 (2010). "Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease" . Sci Transl Med . 2 (28 ): 28ra28. doi :10.1126/scitranslmed.3000664 . PMC 2933751 . PMID 20410529 .
^ Fong AM, Premont RT, Richardson RM, Yu YR, Lefkowitz RJ, Patel DD (2002). "Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice" . Proc Natl Acad Sci USA . 99 (11 ): 7478–7483. Bibcode :2002PNAS...99.7478F . doi :10.1073/pnas.112198299 . PMC 124256 . PMID 12032308 .
^ Kavelaars A, Vroon A, Raatgever RP, Fong AM, Premont RT, Patel DD, Lefkowitz RJ, Heijnen CJ (2003). "Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6" . J Immunol . 171 (11 ): 6128–6134. doi :10.4049/jimmunol.171.11.6128 . PMID 14634128 .
Further reading [ edit ]
Bullrich F, Druck T, Kunapuli P, et al. (1995). "Chromosomal mapping of the genes GPRK5 and GPRK6 encoding G protein-coupled receptor kinases GRK5 and GRK6". Cytogenet. Cell Genet . 70 (3–4): 250–4. doi :10.1159/000134045 . PMID 7789183 .
Stoffel RH, Randall RR, Premont RT, et al. (1994). "Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family" . J. Biol. Chem . 269 (45 ): 27791–4. doi :10.1016/S0021-9258(18 )46852-4 . PMID 7961702 .
Loudon RP, Benovic JL (1994). "Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6" . J. Biol. Chem . 269 (36 ): 22691–7. doi :10.1016/S0021-9258(17 )31701-5 . PMID 8077221 .
Benovic JL, Gomez J (1993). "Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family" . J. Biol. Chem . 268 (26 ): 19521–7. doi :10.1016/S0021-9258(19 )36546-9 . PMID 8366096 .
Freedman NJ, Ament AS, Oppermann M, et al. (1997). "Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity" . J. Biol. Chem . 272 (28 ): 17734–43. doi :10.1074/jbc.272.28.17734 . PMID 9211925 .
Loudon RP, Benovic JL (1997). "Altered activity of palmitoylation-deficient and isoprenylated forms of the G protein-coupled receptor kinase GRK6" . J. Biol. Chem . 272 (43 ): 27422–7. doi :10.1074/jbc.272.43.27422 . PMID 9341194 .
Stoffel RH, Inglese J, Macrae AD, et al. (1998). "Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6". Biochemistry . 37 (46 ): 16053–9. doi :10.1021/bi981432d . PMID 9819198 . S2CID 26096361 .
Premont RT, Claing A, Vitale N, et al. (1998). "β2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein" . Proc. Natl. Acad. Sci. U.S.A . 95 (24 ): 14082–7. Bibcode :1998PNAS...9514082P . doi :10.1073/pnas.95.24.14082 . PMC 24330 . PMID 9826657 .
Milcent MD, Christophe T, Rabiet MJ, et al. (1999). "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". Biochem. Biophys. Res. Commun . 259 (1 ): 224–9. doi :10.1006/bbrc.1999.0758 . PMID 10334944 .
Lazari MF, Liu X, Nakamura K, et al. (1999). "Role of G protein-coupled receptor kinases on the agonist-induced phosphorylation and internalization of the follitropin receptor" . Mol. Endocrinol . 13 (6 ): 866–78. doi :10.1210/me.13.6.866 . PMID 10379886 .
Hall RA, Spurney RF, Premont RT, et al. (1999). "G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction" . J. Biol. Chem . 274 (34 ): 24328–34. doi :10.1074/jbc.274.34.24328 . PMID 10446210 .
Brenninkmeijer CB, Price SA, López Bernal A, Phaneuf S (1999). "Expression of G-protein-coupled receptor kinases in pregnant term and non-pregnant human myometrium" . J. Endocrinol . 162 (3 ): 401–8. doi :10.1677/joe.0.1620401 . PMID 10467231 .
Pronin AN, Morris AJ, Surguchov A, Benovic JL (2000). "Synucleins are a novel class of substrates for G protein-coupled receptor kinases" . J. Biol. Chem . 275 (34 ): 26515–22. doi :10.1074/jbc.M003542200 . PMID 10852916 .
Tiruppathi C, Yan W, Sandoval R, et al. (2000). "G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells" . Proc. Natl. Acad. Sci. U.S.A . 97 (13 ): 7440–5. Bibcode :2000PNAS...97.7440T . doi :10.1073/pnas.97.13.7440 . PMC 16564 . PMID 10861009 .
Zhou H, Yan F, Tai HH (2001). "Phosphorylation and desensitization of the human thromboxane receptor-alpha by G protein-coupled receptor kinases". J. Pharmacol. Exp. Ther . 298 (3 ): 1243–51. PMID 11504827 .
Blaukat A, Pizard A, Breit A, et al. (2001). "Determination of bradykinin B2 receptor in vivo phosphorylation sites and their role in receptor function" . J. Biol. Chem . 276 (44 ): 40431–40. doi :10.1074/jbc.M107024200 . PMID 11517230 .
Willets JM, Challiss RA, Nahorski SR (2002). "Endogenous G protein-coupled receptor kinase 6 Regulates M3 muscarinic acetylcholine receptor phosphorylation and desensitization in human SH-SY5Y neuroblastoma cells" . J. Biol. Chem . 277 (18 ): 15523–9. doi :10.1074/jbc.M111217200 . PMID 11856737 .
Grange-Midroit M, García-Sevilla JA, Ferrer-Alcón M, et al. (2002). "G protein-coupled receptor kinases, beta-arrestin-2 and associated regulatory proteins in the human brain: postmortem changes, effect of age and subcellular distribution". Brain Res. Mol. Brain Res . 101 (1–2): 39–51. doi :10.1016/S0169-328X(02 )00144-4 . PMID 12007830 .
PDB gallery
2acx : Crystal Structure of G protein coupled receptor kinase 6 bound to AMPPNP
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t
e
R e t r i e v e d f r o m " https://en.wikipedia.org/w/index.php?title=GRK6&oldid=1215900379 "
C a t e g o r i e s :
● G e n e s o n h u m a n c h r o m o s o m e 5
● E C 2 . 7 . 1 1
● H u m a n c h r o m o s o m e 5 g e n e s t u b s
H i d d e n c a t e g o r i e s :
● A r t i c l e s w i t h s h o r t d e s c r i p t i o n
● S h o r t d e s c r i p t i o n m a t c h e s W i k i d a t a
● A l l s t u b a r t i c l e s
● T h i s p a g e w a s l a s t e d i t e d o n 2 7 M a r c h 2 0 2 4 , a t 2 0 : 3 4 ( U T C ) .
● T e x t i s a v a i l a b l e u n d e r t h e C r e a t i v e C o m m o n s A t t r i b u t i o n - S h a r e A l i k e L i c e n s e 4 . 0 ;
a d d i t i o n a l t e r m s m a y a p p l y . B y u s i n g t h i s s i t e , y o u a g r e e t o t h e T e r m s o f U s e a n d P r i v a c y P o l i c y . W i k i p e d i a ® i s a r e g i s t e r e d t r a d e m a r k o f t h e W i k i m e d i a F o u n d a t i o n , I n c . , a n o n - p r o f i t o r g a n i z a t i o n .
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