G protein-coupled receptor kinase 3

G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2 gene.[5] GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.[6]

GRK3
Identifiers
AliasesGRK3, BARK2, ADRBK2, Beta adrenergic receptor kinase-2, G protein-coupled receptor kinase 3
External IDsOMIM: 109636 MGI: 87941 HomoloGene: 21072 GeneCards: GRK3
Orthologs
SpeciesHumanMouse
Entrez

157

320129

Ensembl

ENSG00000100077

ENSMUSG00000042249

UniProt

P35626

Q3UYH7

RefSeq (mRNA)

NM_005160
NM_001362778

NM_001035531
NM_001285806
NM_177078

RefSeq (protein)

NP_005151
NP_001349707

NP_001272735
NP_796052

Location (UCSC)Chr 22: 25.56 – 25.73 MbChr 5: 113.06 – 113.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7]

GRK3 and the closely related GRK2 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to GRK5 and GRK6, which have the opposite effect).[8][9] 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.[10][11]

GRK3 is expressed broadly in tissues, but generally at lower levels than the related GRK2.[12] GRK3 has particularly high expression in olfactory neurons, and mice lacking the ADRBK2 gene exhibit defects in olfaction.[13][14] Gene linkage techniques were used to identify a polymorphism in the promoter of the human ADRBK2 gene as a possible cause of up to 10% of cases of bipolar disorder.[15] However, the significance of GRK3 in bipolar disorder has been controversial due to conflicting reports.[16] GRK3 has also been implicated in regulation of dopamine receptors in Parkinson disease in animal models.[17] Reduced expression of GRK3 has been associated with the immunodeficient WHIM syndrome in humans, and appears causative in a mouse model of the disease.[18][19]

References
  1. GRCh38: Ensembl release 89: ENSG00000100077 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000042249 - Ensembl, 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. Calabrese G, Sallese M, Stornaiuolo A, Stuppia L, Palka G, De Blasi A (September 1994). "Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes". Genomics. 23 (1): 286–8. doi:10.1006/geno.1994.1497. PMID 7695743.
  6. Benovic JL, Onorato JJ, Arriza JL, Stone WC, Lohse M, Jenkins NA, Gilbert DJ, Copeland NG, Caron MG, Lefkowitz RJ (August 1991). "Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family". The Journal of Biological Chemistry. 266 (23): 14939–46. doi:10.1016/S0021-9258(18)98568-6. PMID 1869533.
  7. Gurevich VV, Gurevich EV (2019). "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Frontiers in Pharmacology. 10: 125. doi:10.3389/fphar.2019.00125. PMC 6389790. PMID 30837883.
  8. Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ (February 2005). "Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling". Proceedings of the National Academy of Sciences of the United States of America. 102 (5): 1442–7. Bibcode:2005PNAS..102.1442K. doi:10.1073/pnas.0409532102. PMC 547874. PMID 15671181.
  9. Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ (February 2005). "Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor". Proceedings of the National Academy of Sciences of the United States of America. 102 (5): 1448–53. Bibcode:2005PNAS..102.1448R. doi:10.1073/pnas.0409534102. PMC 547876. PMID 15671180.
  10. Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ (June 2009). "Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands". Proceedings of the National Academy of Sciences of the United States of America. 106 (24): 9649–54. Bibcode:2009PNAS..106.9649Z. doi:10.1073/pnas.0904361106. PMC 2689814. PMID 19497875.
  11. Choi M, Staus DP, Wingler LM, Ahn S, Pani B, Capel WD, Lefkowitz RJ (August 2018). "2-adrenergic receptor". Science Signaling. 11 (544). doi:10.1126/scisignal.aar7084. PMID 30131371.
  12. Arriza JL, Dawson TM, Simerly RB, Martin LJ, Caron MG, Snyder SH, Lefkowitz RJ (October 1992). "The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain". The Journal of Neuroscience. 12 (10): 4045–55. doi:10.1523/JNEUROSCI.12-10-04045.1992. PMC 6575981. PMID 1403099.
  13. Boekhoff I, Inglese J, Schleicher S, Koch WJ, Lefkowitz RJ, Breer H (January 1994). "Olfactory desensitization requires membrane targeting of receptor kinase mediated by beta gamma-subunits of heterotrimeric G proteins". The Journal of Biological Chemistry. 269 (1): 37–40. doi:10.1016/S0021-9258(17)42306-4. PMID 8276821.
  14. Ihara S, Touhara K (2018). "G Protein-Coupled Receptor Kinase 3 (GRK3) in Olfaction". Olfactory Receptors. Methods in Molecular Biology. Vol. 1820. pp. 33–41. doi:10.1007/978-1-4939-8609-5_3. ISBN 978-1-4939-8608-8. PMID 29884935.
  15. Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Alexander M, Shaw SH, Kelsoe JR (May 2003). "Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder". Molecular Psychiatry. 8 (5): 546–57. doi:10.1038/sj.mp.4001268. PMID 12808434.
  16. Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA (June 2010). "The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies". European Neuropsychopharmacology. 20 (6): 357–68. doi:10.1016/j.euroneuro.2010.02.008. PMID 20226637. S2CID 43214075.
  17. Ahmed MR, Bychkov E, Li L, Gurevich VV, Gurevich EV (June 2015). "GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson's disease via its RGS homology domain". Scientific Reports. 5: 10920. Bibcode:2015NatSR...510920A. doi:10.1038/srep10920. PMC 4455246. PMID 26043205.
  18. Balabanian K, Levoye A, Klemm L, Lagane B, Hermine O, Harriague J, Baleux F, Arenzana-Seisdedos F, Bachelerie F (March 2008). "Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling". The Journal of Clinical Investigation. 118 (3): 1074–84. doi:10.1172/JCI33187. PMC 2242619. PMID 18274673.
  19. Tarrant TK, Billard MJ, Timoshchenko RG, McGinnis MW, Serafin DS, Foreman O, Esserman DA, Chao NJ, Lento WE, Lee DM, Patel D, Siderovski DP (December 2013). "G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses". Journal of Leukocyte Biology. 94 (6): 1243–51. doi:10.1189/jlb.0213097. PMC 3828605. PMID 23935208.

Further reading
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