G protein-coupled receptor kinase

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
G protein-coupled receptor kinase
Gprotein-coupled receptor kinase.png
Crystal structure of G protein coupled receptor kinase 1 (GRK1) bound to ATP.[1]
Identifiers
EC number2.7.11.16
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

G protein-coupled receptor kinases (GRKs, GPCRKs) are a family of protein kinases within the AGC (protein kinase A, protein kinase G, protein kinase C) group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.[2][3]

Types of GRKs[edit]

Name Notes Gene OMIM
G protein-coupled receptor kinase 1 Rhodopsin kinase GRK1 180381
G protein-coupled receptor kinase 2 β-Adrenergic receptor kinase 1 (βARK1) ADRBK1 109635
G protein-coupled receptor kinase 3 β-Adrenergic receptor kinase 2 (βARK2) ADRBK2 109636
G protein-coupled receptor kinase 4 Polymorphism associated with hypertension[4] GRK4 137026
G protein-coupled receptor kinase 5 Polymorphism associated with cardioprotection[5] GRK5 600870
G protein-coupled receptor kinase 6 Knockout mice are supersensitive to dopaminergic drugs[6] GRK6 600869
G protein-coupled receptor kinase 7 Cone opsin kinase GRK7 606987

GRK Activity and Regulation[edit]

GRKs reside normally in an inactive state, but their kinase activity is stimulated by binding to a ligand-activated GPCR (rather than by regulatory phosphorylation as is common in other AGC kinases). Because there are only seven GRKs (only 4 of which are widely expressed throughout the body) but over 800 human GPCRs, GRKs appear to have limited phosphorylation site selectivity and are regulated primarily by the GPCR active state.[3]

G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Phosphorylated serine and threonine residues in GPCRs act as binding sites for and activators of arrestin proteins. 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]

GRKs can be regulated by signaling events in cells, both in direct feedback mechanisms where receptor signals alter GRK activity over time, and due to signals emanating from distinct pathways from a particular GPCR/GRK system of interest. For example, GRK1 is regulated by the calcium sensor protein recoverin: calcium-bound recoverin binds directly to GRK1 to inhibit its ability to phosphorylate and desensitize rhodopsin, the visual GPCR in the retina, in light-activated retinal rod cells since light activation raises intracellular calcium in these cells, whereas in dark-adapted eyes, calcium levels are low in rod cells and GRK1 is not inhibited by recoverin.[7] The non-visual GRKs are inhibited instead by the calcium-binding protein calmodulin.[2] GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein beta/gamma subunits, and GPCR activation of heterotrimeric G proteins releases this free beta/gamma 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.[2][3] GRK2 activity can be modulated by its phosphorylation by protein kinase A or protein kinase C, and by post-translational modification of cysteines by S-nitrosylation.[8][9]

GRK Structures[edit]

X-ray crystal structures have been obtained for several GRKs (GRK1, GRK2, GRK4, GRK5 and GRK6), alone or bound to ligands.[10] Overall, GRKs share sequence homology and domain organization in which the central protein kinase catalytic domain is preceded by a domain with homology to the active domain of Regulator of G protein Signaling proteins, RGS proteins (the RGS-homology – RH – domain) and is followed by a variable carboxyl terminal tail regulatory region.[3] In the folded proteins, the kinase domain forms a typical bi-lobe kinase structure with a central ATP-binding active site.[3] The RH domain is composed of alpha-helical region formed from the amino terminal sequence plus a short stretch of sequence following the kinase domain that provides 2 additional helices, and makes extensive contacts with one side of the kinase domain.[10] Modeling and mutagenesis suggests that the RH domain senses GPCR activation to open the kinase active site.[11]

GRK Physiological Functions[edit]

GRK1 is involved with rhodopsin phosphorylation and deactivation in vision, together with arrestin-1, also known as S-antigen. Defects in GRK1 result in Oguchi stationary night blindness. GRK7 similarly regulates cone opsin phosphorylation and deactivation in color vision, together with cone arrestin, also known as arrestin-4 or X-arrestin.[3]

GRK2 was first identified as an enzyme that phosphorylated the beta-2 adrenergic receptor, and was originally called the beta adrenergic receptor kinase (βARK, or ββARK1). GRK2 is overexpressed in heart failure, and GRK2 inhibition could be used to treat heart failure in the future.[12]

Polymorphisms in the GRK4 gene have been linked to both genetic and acquired hypertension, acting in part through kidney dopamine receptors. [4] GRK4 is the most highly expressed GRK at the mRNA level, in maturing spermatids, but mice lacking GRK4 remain fertile so its role in these cells remains unknown.[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 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.[15]

In the mouse, GRK6 regulation of D2 dopamine receptors in the striatum region of the brain alters sensitivity to psychostimulant drugs that act through dopamine, and GRK6 has been implicated in Parkinson’s disease and in the dyskinesia side effects of anti-parkinson therapy with the drug L-DOPA.[16][17]

Non-GPCR Functions of GRKs[edit]

GRKs also phosphorylate non-GPCR substrates. GRK2 and GRK5 can phosphorylate some tyrosine kinase receptors, including the receptor for platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF).[18][19]

GRKs also regulate cellular responses independent of their kinase activity. In particular, G protein-coupled receptor kinase 2 is known to interact with a diverse repertoire of non-GPCR partner proteins, but other GRKs also have non-GPCR partners.[20] The RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family, but despite these RH domains being unable to act as GTPase-activating proteins like traditional RGS proteins to turn off G protein signaling, this binding reduces Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta.[21]

See also[edit]

References[edit]

  1. ^ PDB: 3C4W​; Singh P, Wang B, Maeda T, Palczewski K, Tesmer JJ (May 2008). "Structures of rhodopsin kinase in different ligand states reveal key elements involved in G protein-coupled receptor kinase activation". J. Biol. Chem. 283 (20): 14053–62. doi:10.1074/jbc.M708974200. PMC 2376226. PMID 18339619.
  2. ^ a b c Ribas C, Penela P, Murga C, Salcedo A, García-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr (2007). "The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling". Biochim Biophys Acta. 1768 (4): 913–922. doi:10.1016/j.bbamem.2006.09.019. PMID 17084806.
  3. ^ a b c d e f g Gurevich VV, Gurevich EV (2019). "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Front Pharmacol. 10. doi:10.3389/fphar.2019.00125. PMC 6389790. PMID 30837883.
  4. ^ a b Yang J, Villar VA, Jones JE, Jose PA, Zeng C (2015). "G protein-coupled receptor kinase 4: role in hypertension". Hypertension. 65 (6): 1148–1155. doi:10.1161/HYPERTENSIONAHA.115.05189. PMID 25870190.
  5. ^ Dorn GW 2nd, Liggett SB (2008). "Pharmacogenomics of beta-adrenergic receptors and their accessory signaling proteins in heart failure". Clin Transl Sci. 1 (3): 255–262. doi:10.1111/j.1752-8062.2008.00059.x. PMC 5350665. PMID 20443857.
  6. ^ Gainetdinov RR, Bohn LM, Sotnikova TD, et al. (April 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.
  7. ^ Chen CK, Inglese J, Lefkowitz RJ, Hurley JB (July 1995). "Ca(2+)-dependent interaction of recoverin with rhodopsin kinase". The Journal of Biological Chemistry. 270 (30): 18060–6. doi:10.1074/jbc.270.30.18060. PMID 7629115.
  8. ^ Willets JM, Challiss RA, Nahorski SR (2003). "Non-visual GRKs: are we seeing the whole picture?". Trends Pharmacol Sci. 24 (12): 626–633. doi:10.1016/j.tips.2003.10.003. PMID 14654303.
  9. ^ Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS (2007). "Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2". Cell. 129 (3): 511–522. doi:10.1016/j.cell.2007.02.046. PMID 17482545.
  10. ^ a b Homan KT, Tesmer JJ (2015). "Molecular basis for small molecule inhibition of G protein-coupled receptor kinases". ACS Chem Biol. 10 (1): 246–256. doi:10.1021/cb5003976. PMC 4301174. PMID 24984143.
  11. ^ He Y, Gao X, Goswami D, Hou L, Pal K, Yin Y, Zhao G, Ernst OP, Griffin P, Melcher K, Xu HE (2017). "Molecular assembly of rhodopsin with G protein-coupled receptor kinases". Cell Res. 27 (6): 728–747. doi:10.1038/cr.2017.72. PMID 28524165.
  12. ^ Tesmer, J. J.; Koch, W. J.; Sklar, L. A.; Cheung, J. Y.; Gao, E.; Song, J.; Chuprun, J. K.; Huang, Z. M.; Hinkle, P. M. (2012). "Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility". ACS Chemical Biology. 7 (11): 1830–1839. doi:10.1021/cb3003013. ISSN 1554-8929. PMC 3500392. PMID 22882301.
  13. ^ Premont RT, Macrae AD, Stoffel RH, et al. (1996). "Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants". J. Biol. Chem. 271 (11): 6403–10. doi:10.1074/jbc.271.11.6403. PMID 8626439.
  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". Pharmacogenet Genomics. 18 (8): 729–732. doi:10.1097/FPC.0b013e32830967e9. PMID 18622265.
  15. ^ 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". Sci Rep. 6: 33231. doi:10.1038/srep33231. PMID 27618959.
  16. ^ 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.
  17. ^ 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. PMID 20410529.
  18. ^ Wu JH, Goswami R, Cai X, Exum ST, Huang X, Zhang L, Brian L, Premont RT, Peppel K, Freedman NJ (2006). "Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2". J Biol Chem. 281 (49): 37758–37772. doi:10.1074/jbc.M605756200. PMID 17018529.
  19. ^ Zheng H, Worrall C, Shen H, Issad T, Seregard S, Girnita A, Girnita L (2012). "Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor". Proc Natl Acad Sci USA. 109 (18): 7055–7060. doi:10.1073/pnas.1118359109. PMID 22509025.
  20. ^ Evron T, Daigle TL, Caron MG (March 2012). "GRK2: multiple roles beyond G protein-coupled receptor desensitization". Trends Pharmacol. Sci. 33 (3): 154–64. doi:10.1016/j.tips.2011.12.003. PMC 3294176. PMID 22277298..
  21. ^ Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ (2005). "Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex". Science. 310 (5754): 1686–1690. doi:10.1126/science.1118890. PMID 16339447.

Further reading[edit]