Biology:GRK6

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1][2][3] 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.[4]

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).[5][6] 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.[7][8]

GRK6 is widely and relatively evenly expressed throughout the body, but with particularly high expression in immune cells.[2] 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.[9] 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.[10] 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.[11] In mouse immune cells, GRK6 is important for chemotaxis of B-lymphocytes and T-lymphocytes in response to the chemoattractant CXCL12,[12] and of neutrophils to sites of injury in response to leukotriene B4.[13]

References

  1. ↑ "Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family". J Biol Chem 268 (26): 19521–19527. 1993. doi:10.1016/S0021-9258(19)36546-9. PMID 8366096. 
  2. ↑ 2.0 2.1 "Identification of additional members of human G-protein-coupled receptor kinase multigene family". Proc Natl Acad Sci USA 90 (20): 9398–9402. 1993. doi:10.1073/pnas.90.20.9398. PMID 8415712. Bibcode: 1993PNAS...90.9398H. 
  3. ↑ "Protein kinases that phosphorylate activated G protein-coupled receptors". FASEB J 9 (2): 175–182. 1995. doi:10.1096/fasebj.9.2.7781920. PMID 7781920. 
  4. ↑ "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Front Pharmacol 10: 125. 2019. doi:10.3389/fphar.2019.00125. PMID 30837883. 
  5. ↑ "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. 2005. doi:10.1073/pnas.0409532102. PMID 15671181. Bibcode: 2005PNAS..102.1442K. 
  6. ↑ "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. 2005. doi:10.1073/pnas.0409534102. PMID 15671180. Bibcode: 2005PNAS..102.1448R. 
  7. ↑ "Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands". Proc Natl Acad Sci USA 106 (24): 9649–9654. 2009. doi:10.1073/pnas.0904361106. PMID 19497875. Bibcode: 2009PNAS..106.9649Z. 
  8. ↑ "G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor". Sci Signal 11 (544): eaar7084. 2018. doi:10.1126/scisignal.aar7084. PMID 30131371. 
  9. ↑ "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation". J Biol Chem 274 (41): 29381–29389. 1999. doi:10.1074/jbc.274.41.29381. PMID 10506199. 
  10. ↑ "Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice". Neuron 38 (2): 291–303. 2003. doi:10.1016/S0896-6273(03)00192-2. PMID 12718862. 
  11. ↑ "Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease". Sci Transl Med 2 (28): 28ra28. 2010. doi:10.1126/scitranslmed.3000664. PMID 20410529. 
  12. ↑ "Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice". Proc Natl Acad Sci USA 99 (11): 7478–7483. 2002. doi:10.1073/pnas.112198299. PMID 12032308. Bibcode: 2002PNAS...99.7478F. 
  13. ↑ "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. 2003. doi:10.4049/jimmunol.171.11.6128. PMID 14634128. 

Further reading




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