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GRK6

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GRK6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGRK6, GPRK6, G protein-coupled receptor kinase 6
External IDsOMIM: 600869; MGI: 1347078; HomoloGene: 37570; GeneCards: GRK6; OMA:GRK6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001004105
NM_001004106
NM_002082
NM_001364164

RefSeq (protein)

NP_001004105
NP_001004106
NP_002073
NP_001351093

Location (UCSC)Chr 5: 177.4 – 177.44 MbChr 13: 55.59 – 55.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198055Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000074886Ensembl, 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. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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

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