Biology:G protein-coupled receptor kinase 2

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Short description: Enzyme


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


G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene.[1] GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).[2]

Functions

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.[3]

GRK2 and the closely related GRK3 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).[4][5] 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.[6][7]

GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3.[8] GRK2 was originally identified as a protein kinase that phosphorylated the β2-adrenergic receptor, and has been most extensively studied as a regulator of adrenergic receptors (and other GPCRs) in the heart, where it has been proposed as a drug target to treat heart failure.[9][10] Strategies to inhibit GRK2 include using small molecules (including Paroxetine and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminal pleckstrin-homology (PH) domain that binds the G protein βγ-subunit complex and inhibits GRK2 activation (often called the “βARKct”), or just a peptide from this PH domain).[11][9]

GRK2 and the related GRK3 can interact with heterotrimeric G protein subunits resulting from GPCR activation, both to be activated and to regulate G protein signaling pathways. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein βγ subunits, and GPCR activation of heterotrimeric G proteins releases this free βγ complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor.[12][3] The amino terminal RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family to reduce Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta; but the GRK2 and GRK3 RH domains are unable to function as GTPase-activating proteins (as do traditional RGS proteins) to turn off G protein signaling.[13]

Interactions

GRK2 has been shown to interact with numerous protein partners,[14][15][16] including:


See also

References

  1. ↑ "Beta-adrenergic receptor kinase: primary structure delineates a multigene family". Science 246 (4927): 235–240. 1989. doi:10.1126/science.2552582. PMID 2552582. Bibcode: 1989Sci...246..235B. 
  2. ↑ Benovic JL; Onorato JJ; Arriza JL et al. (1991). "Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family". J. Biol. Chem. 266 (23): 14939–14946. doi:10.1016/S0021-9258(18)98568-6. PMID 1869533. 
  3. ↑ 3.0 3.1 "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Front Pharmacol 10: 125. 2019. doi:10.3389/fphar.2019.00125. PMID 30837883. 
  4. ↑ "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. 
  5. ↑ "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. 
  6. ↑ "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. 
  7. ↑ "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. 
  8. ↑ "The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain". J Neurosci 12 (10): 4045–4055. 1992. doi:10.1523/jneurosci.12-10-04045.1992. PMID 1403099. 
  9. ↑ 9.0 9.1 "GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy". Expert Opin Ther Targets 23 (3): 201–214. 2019. doi:10.1080/14728222.2019.1575363. PMID 30701991. 
  10. ↑ "G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases". Front Pharmacol 10: 112. 2019. doi:10.3389/fphar.2019.00112. PMID 30837878. 
  11. ↑ "Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility". ACS Chem Biol 7 (11): 1830–1839. 2012. doi:10.1021/cb3003013. PMID 22882301. 
  12. ↑ "The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling". Biochim Biophys Acta 1768 (4): 913–922. 2007. doi:10.1016/j.bbamem.2006.09.019. PMID 17084806. 
  13. ↑ 13.0 13.1 "Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex". Science 310 (5754): 1686–1690. 2005. doi:10.1126/science.1118890. PMID 16339447. Bibcode: 2005Sci...310.1686T. 
  14. ↑ "The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development". Pharmacol Res 110: 52–64. 2016. doi:10.1016/j.phrs.2016.05.008. PMID 27180008. 
  15. ↑ "GRK2: multiple roles beyond G protein-coupled receptor desensitization". Trends Pharmacol. Sci. 33 (3): 154–164. March 2012. doi:10.1016/j.tips.2011.12.003. PMID 22277298. .
  16. ↑ "The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets". Br J Pharmacol 160 (4): 821–832. 2010. doi:10.1111/j.1476-5381.2010.00727.x. PMID 20590581. 
  17. ↑ "Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase". Cell 143 (5): 750–760. November 2010. doi:10.1016/j.cell.2010.10.018. PMID 21111235. 
  18. ↑ "Differential interaction of GRK2 with members of the G alpha q family". Biochemistry 42 (30): 9176–9184. August 2003. doi:10.1021/bi034442+. PMID 12885252. 
  19. ↑ "The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing". J. Biol. Chem. 275 (29): 22373–22380. July 2000. doi:10.1074/jbc.275.29.22373. PMID 10896954. 
  20. ↑ "beta2-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): 14082–14087. November 1998. doi:10.1073/pnas.95.24.14082. PMID 9826657. Bibcode: 1998PNAS...9514082P. 
  21. ↑ 21.0 21.1 "The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor". J. Biol. Chem. 278 (20): 18658–18663. May 2003. doi:10.1074/jbc.M212103200. PMID 12624098. 
  22. ↑ "Pleckstrin homology domain of G protein-coupled receptor kinase-2 binds to PKC and affects the activity of PKC kinase". World J. Gastroenterol. 9 (4): 800–803. April 2003. doi:10.3748/wjg.v9.i4.800. PMID 12679936. 

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