Available structures
PDBOrtholog search: PDBe RCSB
AliasesGRK5, GPRK5, G protein-coupled receptor kinase 5, FP2025
External IDsOMIM: 600870; MGI: 109161; HomoloGene: 3879; GeneCards: GRK5; OMA:GRK5 - orthologs
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 10: 119.21 – 119.46 MbChr 19: 60.88 – 61.08 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6.[5][6][7] The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.


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]

GRK5 and the closely related GRK6 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]

GRK5 is widely expressed throughout the body, but with notably high expression in the lung, heart and placenta, with widespread expression at lower levels.[13] In humans, a GRK5 sequence polymorphism at residue 41 (leucine rather than glutamine) that is most common in individuals with African ancestry leads to elevated GRK5-mediated desensitization of airway beta2-adrenergic receptors, a drug target in asthma.[14] In the mouse, GRK5 regulates the M2 subtype of Muscarinic acetylcholine receptors in airways and neurons, and mice lacking GRK5 have been proposed as a model for Alzheimer's disease.[15][16][17] In zebrafish and in humans, loss of GRK5 function has been associated with heart defects due to heterotaxy, a series of developmental defects arising from improper left-right laterality during organogenesis.[18] Overexpression of GRK5 in the heart of mice has shown that GRK5 regulates beta2-adrenergic receptors, but GRK5 overexpression or deletion does not affect signaling by the angiotensin II AT1 receptor in the heart.[19][20]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198873Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003228Ensembl, 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. ^ Kunapuli P, Benovic JL (Jun 1993). "Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family". Proceedings of the National Academy of Sciences. 90 (12): 5588–92. Bibcode:1993PNAS...90.5588K. doi:10.1073/pnas.90.12.5588. PMC 46766. PMID 7685906.
  6. ^ Premont RT, Inglese J, Lefkowitz RJ (1995). "Protein kinases that phosphorylate activated G protein-coupled receptors". The FASEB Journal. 9 (2): 175–182. doi:10.1096/fasebj.9.2.7781920. PMID 7781920. S2CID 20428064.
  7. ^ "Entrez Gene: GRK5 G protein-coupled receptor kinase 5".
  8. ^ 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.
  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". Proceedings of the National Academy of Sciences. 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". Proceedings of the National Academy of Sciences. 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". Proceedings of the National Academy of Sciences. 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". Science Signaling. 11 (544): eaar7084. doi:10.1126/scisignal.aar7084. PMID 30131371.
  13. ^ Kunapuli P, Benovic JL (1993). "Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family". Proceedings of the National Academy of Sciences. 90 (12): 5588–5592. Bibcode:1993PNAS...90.5588K. doi:10.1073/pnas.90.12.5588. PMC 46766. PMID 7685906.
  14. ^ Wang WC, Mihlbachler KA, Bleecker ER, Weiss ST, Liggett SB (2008). "A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of beta2-adrenergic receptors". Pharmacogenetics and Genomics. 18 (8): 729–732. doi:10.1097/FPC.0b013e32830967e9. PMC 2699179. PMID 18622265.
  15. ^ Gainetdinov RR, Bohn LM, Walker JK, Laporte SA, Macrae AD, Caron MG, Lefkowitz RJ, Premont RT (1999). "Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice". Neuron. 24 (4): 1029–1036. doi:10.1016/S0896-6273(00)81048-X. PMID 10624964. S2CID 7788715.
  16. ^ Walker JK, Gainetdinov RR, Feldman DS, McFawn PK, Caron MG, Lefkowitz RJ, Premont RT, Fisher JT (2004). "G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation". American Journal of Physiology. Lung Cellular and Molecular Physiology. 286 (2): L312–L319. doi:10.1152/ajplung.00255.2003. PMID 14565944.
  17. ^ He M, Singh P, Cheng S, Zhang Q, Peng W, Ding X, Li L, Liu J, Premont RT, Morgan D, Burns JM, Swerdlow RH, Suo WZ (2016). "GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability". Scientific Reports. 6: 26116. Bibcode:2016NatSR...626116H. doi:10.1038/srep26116. PMC 4872166. PMID 27193825.
  18. ^ Lessel D, Muhammad T, Casar Tena T, Moepps B, Burkhalter MD, Hitz MP, Toka O, Rentzsch A, Schubert S, Schalinski A, Bauer UM, Kubisch C, Ware SM, Philipp M (2016). "The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5". Scientific Reports. 6: 33231. Bibcode:2016NatSR...633231L. doi:10.1038/srep33231. PMC 5020398. PMID 27618959.
  19. ^ Rockman HA, Choi DJ, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ (1996). "Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice". Proceedings of the National Academy of Sciences. 93 (18): 9954–9959. Bibcode:1996PNAS...93.9954R. doi:10.1073/pnas.93.18.9954. PMC 38536. PMID 8790438.
  20. ^ Rajagopal K, Whalen EJ, Violin JD, Stiber JA, Rosenberg PB, Premont RT, Coffman TM, Rockman HA, Lefkowitz RJ (2006). "Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes". Proceedings of the National Academy of Sciences. 103 (44): 16284–16289. Bibcode:2006PNAS..10316284R. doi:10.1073/pnas.0607583103. PMC 1637574. PMID 17060617.

Further reading