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Gene Review

GRK1  -  G protein-coupled receptor kinase 1

Homo sapiens

Synonyms: GPRK1, RHOK, RK, Rhodopsin kinase
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Disease relevance of GRK1

  • The relationship between myocardial G protein receptor kinase (GRK) expression and beta-adrenoceptor signalling in human left heart diseases has not been fully elucidated yet [1].
  • G-protein-coupled receptor kinase activity is increased in hypertension [2].
  • To date, three different mutations in the RK locus have been associated with Oguchi disease, an autosomal recessive form of stationary night blindness in man characterized in part by delayed photoreceptor recovery [Yamamoto, S. , Sippel, K. C., Berson, E. L. & Dryja, T. P. (1997) Nat. Genet. 15, 175-178] [3].
  • Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants [4].
  • The GRK and PKA site antibodies were also effective in detecting phosphorylation of the endogenous beta2AR expressed in A431 human epidermoid carcinoma cells [5].

Psychiatry related information on GRK1


High impact information on GRK1

  • Our results identify a new role for PDZ-domain-mediated protein interactions and for the actin cytoskeleton in endocytic sorting, and suggest a mechanism by which GRK-mediated phosphorylation could regulate membrane trafficking of G-protein-coupled receptors after endocytosis [9].
  • We show that overexpression of rhodopsin kinase (GRK1) increases phosphorylation of the GPCR rhodopsin but has no effect on photoresponse recovery [10].
  • Here we investigate whether GRK or RGS governs the overall rate of recovery of the light response in mammalian rod photoreceptors, a model system for studying GPCR signaling [10].
  • In cone-dominant animals as well as in humans, but not in rodents, GRK7, a cone-specific homolog of GRK1, has been identified in cone outer segments [11].
  • Phosphorylation of rhodopsin by rhodopsin kinase GRK1 is an important desensitization mechanism in scotopic vision [11].

Chemical compound and disease context of GRK1


Biological context of GRK1

  • Human photoreceptors also transcribe a splice variant of GRK1, which differs in its C-terminal region next to the catalytic domain [16].
  • Among these enzymes, GRK1 (rhodopsin kinase) is involved in phototransduction and is the most specialized of the family [16].
  • Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient [17].
  • It remains unclear why the loss of GRK1 yields such different phenotypes in the recovery of mouse and human cones [18].
  • The disease in the Pakistani family localizes to 13q34 and is caused by a novel deletion including Exon 3 of the GRK1 gene [19].

Anatomical context of GRK1

  • Thus, these studies suggest that rods and cones, express the same form of GRK1 [16].
  • Based on results of molecular cloning and immunolocalization, it appears that both rod and cone photoreceptors express GRK1 [16].
  • This novel variant, GRK1b, is produced by retention of the last intron. mRNA encoding GRK1b is exported to the cytosol; however, the level of the protein is relatively low compared with GRK1 (now called GRK1a), and GRK1b appears to have very low catalytic activity [16].
  • Rod outer segments isolated from bovine retina phosphorylated the FLAG-tagged GRKs in the presence of dibutyryl-cAMP, suggesting that GRK1 and GRK7 are physiologically relevant substrates [20].
  • These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects [2].

Associations of GRK1 with chemical compounds

  • G protein-coupled receptor kinase-mediated desensitization of metabotropic glutamate receptor 1A protects against cell death [21].
  • These studies suggest that CSP act as functional analogues in mediating the regulation of different GRK subtypes by Ca(2+) [22].
  • Proline 391 is not only within the functionally important catalytic domain, but is also a phylogenetically conserved amino acid residue among GRK1 orthologs and homologs [23].
  • The ability of these reagents to inhibit GRK- mediated receptor phosphorylation is demonstrated in permeabilized 293 cells that overexpress individual GRKs and the type 1A angiotensin II receptor [24].
  • In this human in vivo condition without a functional RK and probable lack of phosphorylation and arrestin binding to activated rhodopsin, reduction of photolyzed chromophore and regeneration processes with 11-cis-retinal probably constitute the sole pathway for recovery of rod sensitivity [25].

Physical interactions of GRK1


Enzymatic interactions of GRK1


Regulatory relationships of GRK1


Other interactions of GRK1


Analytical, diagnostic and therapeutic context of GRK1


  1. Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases. Dzimiri, N., Muiya, P., Andres, E., Al-Halees, Z. Eur. J. Pharmacol. (2004) [Pubmed]
  2. G-protein-coupled receptor kinase activity is increased in hypertension. Gros, R., Benovic, J.L., Tan, C.M., Feldman, R.D. J. Clin. Invest. (1997) [Pubmed]
  3. Biochemical evidence for pathogenicity of rhodopsin kinase mutations correlated with the oguchi form of congenital stationary night blindness. Khani, S.C., Nielsen, L., Vogt, T.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Arraes, S.M., Freitas, M.S., da Silva, S.V., de Paula Neto, H.A., Alves-Filho, J.C., Martins, M.A., Basile-Filho, A., Tavares-Murta, B.M., Barja-Fidalgo, C., Cunha, F.Q. Blood (2006) [Pubmed]
  5. Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the beta2-adrenergic receptor using phosphoserine-specific antibodies. Tran, T.M., Friedman, J., Qunaibi, E., Baameur, F., Moore, R.H., Clark, R.B. Mol. Pharmacol. (2004) [Pubmed]
  6. Pathophysiological roles of G-protein-coupled receptor kinases. Métayé, T., Gibelin, H., Perdrisot, R., Kraimps, J.L. Cell. Signal. (2005) [Pubmed]
  7. RhoA-mediated Ca2+ sensitization in erectile function. Wang, H., Eto, M., Steers, W.D., Somlyo, A.P., Somlyo, A.V. J. Biol. Chem. (2002) [Pubmed]
  8. Chronic treatment with mood stabilizers increases membrane GRK3 in rat frontal cortex. Ertley, R.N., Bazinet, R.P., Lee, H.J., Rapoport, S.I., Rao, J.S. Biol. Psychiatry (2007) [Pubmed]
  9. A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor. Cao, T.T., Deacon, H.W., Reczek, D., Bretscher, A., von Zastrow, M. Nature (1999) [Pubmed]
  10. RGS expression rate-limits recovery of rod photoresponses. Krispel, C.M., Chen, D., Melling, N., Chen, Y.J., Martemyanov, K.A., Quillinan, N., Arshavsky, V.Y., Wensel, T.G., Chen, C.K., Burns, M.E. Neuron (2006) [Pubmed]
  11. Knockdown of cone-specific kinase GRK7 in larval zebrafish leads to impaired cone response recovery and delayed dark adaptation. Rinner, O., Makhankov, Y.V., Biehlmaier, O., Neuhauss, S.C. Neuron (2005) [Pubmed]
  12. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. Wahl, S., Barth, H., Ciossek, T., Aktories, K., Mueller, B.K. J. Cell Biol. (2000) [Pubmed]
  13. The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase. Schmidmaier, R., Baumann, P., Simsek, M., Dayyani, F., Emmerich, B., Meinhardt, G. Blood (2004) [Pubmed]
  14. Cyclic AMP blocks bacterial lipopolysaccharide-induced myosin light chain phosphorylation in endothelial cells through inhibition of Rho/Rho kinase signaling. Essler, M., Staddon, J.M., Weber, P.C., Aepfelbacher, M. J. Immunol. (2000) [Pubmed]
  15. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. McLaughlin, J.N., Shen, L., Holinstat, M., Brooks, J.D., Dibenedetto, E., Hamm, H.E. J. Biol. Chem. (2005) [Pubmed]
  16. Molecular forms of human rhodopsin kinase (GRK1). Zhao, X., Huang, J., Khani, S.C., Palczewski, K. J. Biol. Chem. (1998) [Pubmed]
  17. Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3. Cideciyan, A.V., Jacobson, S.G., Gupta, N., Osawa, S., Locke, K.G., Weiss, E.R., Wright, A.F., Birch, D.G., Milam, A.H. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  18. Characterization of human GRK7 as a potential cone opsin kinase. Chen, C.K., Zhang, K., Church-Kopish, J., Huang, W., Zhang, H., Chen, Y.J., Frederick, J.M., Baehr, W. Mol. Vis. (2001) [Pubmed]
  19. A variant form of Oguchi disease mapped to 13q34 associated with partial deletion of GRK1 gene. Zhang, Q., Zulfiqar, F., Riazuddin, S.A., Xiao, X., Yasmeen, A., Rogan, P.K., Caruso, R., Sieving, P.A., Riazuddin, S., Hejtmancik, J.F. Mol. Vis. (2005) [Pubmed]
  20. Phosphorylation of GRK1 and GRK7 by cAMP-dependent protein kinase attenuates their enzymatic activities. Horner, T.J., Osawa, S., Schaller, M.D., Weiss, E.R. J. Biol. Chem. (2005) [Pubmed]
  21. G protein-coupled receptor kinase-mediated desensitization of metabotropic glutamate receptor 1A protects against cell death. Dale, L.B., Bhattacharya, M., Anborgh, P.H., Murdoch, B., Bhatia, M., Nakanishi, S., Ferguson, S.S. J. Biol. Chem. (2000) [Pubmed]
  22. Regulation of G protein-coupled receptor kinase subtypes by calcium sensor proteins. Sallese, M., Iacovelli, L., Cumashi, A., Capobianco, L., Cuomo, L., De Blasi, A. Biochim. Biophys. Acta (2000) [Pubmed]
  23. A Novel Homozygous GRK1 Mutation (P391H) in 2 Siblings with Oguchi Disease with Markedly Reduced Cone Responses. Hayashi, T., Gekka, T., Takeuchi, T., Goto-Omoto, S., Kitahara, K. Ophthalmology (2007) [Pubmed]
  24. Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases. Oppermann, M., Diversé-Pierluissi, M., Drazner, M.H., Dyer, S.L., Freedman, N.J., Peppel, K.C., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  25. Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man. Cideciyan, A.V., Zhao, X., Nielsen, L., Khani, S.C., Jacobson, S.G., Palczewski, K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Regulation of rhodopsin kinase by autophosphorylation. Buczyłko, J., Gutmann, C., Palczewski, K. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  27. Autophosphorylation and ADP regulate the Ca2+-dependent interaction of recoverin with rhodopsin kinase. Satpaev, D.K., Chen, C.K., Scotti, A., Simon, M.I., Hurley, J.B., Slepak, V.Z. Biochemistry (1998) [Pubmed]
  28. Rhodopsin arginine-135 mutants are phosphorylated by rhodopsin kinase and bind arrestin in the absence of 11-cis-retinal. Shi, W., Sports, C.D., Raman, D., Shirakawa, S., Osawa, S., Weiss, E.R. Biochemistry (1998) [Pubmed]
  29. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Zhao, Z.S., Manser, E., Loo, T.H., Lim, L. Mol. Cell. Biol. (2000) [Pubmed]
  30. Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration. Ménard, L., Ferguson, S.S., Barak, L.S., Bertrand, L., Premont, R.T., Colapietro, A.M., Lefkowitz, R.J., Caron, M.G. Biochemistry (1996) [Pubmed]
  31. G-protein-coupled receptor kinase specificity for beta-arrestin recruitment to the beta2-adrenergic receptor revealed by fluorescence resonance energy transfer. Violin, J.D., Ren, X.R., Lefkowitz, R.J. J. Biol. Chem. (2006) [Pubmed]
  32. Functional significance of the specific sites phosphorylated in desmin at cleavage furrow: Aurora-B may phosphorylate and regulate type III intermediate filaments during cytokinesis coordinatedly with Rho-kinase. Kawajiri, A., Yasui, Y., Goto, H., Tatsuka, M., Takahashi, M., Nagata, K., Inagaki, M. Mol. Biol. Cell (2003) [Pubmed]
  33. New aspects of neurotransmitter release and exocytosis: Rho-kinase-dependent myristoylated alanine-rich C-kinase substrate phosphorylation and regulation of neurofilament structure in neuronal cells. Sasaki, Y. J. Pharmacol. Sci. (2003) [Pubmed]
  34. Protein kinases that phosphorylate activated G protein-coupled receptors. Premont, R.T., Inglese, J., Lefkowitz, R.J. FASEB J. (1995) [Pubmed]
  35. Role of G protein-coupled receptor kinases on the agonist-induced phosphorylation and internalization of the follitropin receptor. Lazari, M.F., Liu, X., Nakamura, K., Benovic, J.L., Ascoli, M. Mol. Endocrinol. (1999) [Pubmed]
  36. G protein-coupled receptor kinase interaction with Hsp90 mediates kinase maturation. Luo, J., Benovic, J.L. J. Biol. Chem. (2003) [Pubmed]
  37. Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity. Freedman, N.J., Ament, A.S., Oppermann, M., Stoffel, R.H., Exum, S.T., Lefkowitz, R.J. J. Biol. Chem. (1997) [Pubmed]
  38. G protein-coupled receptor adaptation mechanisms. Ferguson, S.S., Caron, M.G. Semin. Cell Dev. Biol. (1998) [Pubmed]
  39. Identification of additional members of human G-protein-coupled receptor kinase multigene family. Haribabu, B., Snyderman, R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  40. Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family. Kunapuli, P., Benovic, J.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  41. Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. Fredericks, Z.L., Pitcher, J.A., Lefkowitz, R.J. J. Biol. Chem. (1996) [Pubmed]
  42. Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. Lombardi, M.S., Kavelaars, A., Schedlowski, M., Bijlsma, J.W., Okihara, K.L., Van de Pol, M., Ochsmann, S., Pawlak, C., Schmidt, R.E., Heijnen, C.J. FASEB J. (1999) [Pubmed]
  43. GRK1 and GRK7: unique cellular distribution and widely different activities of opsin phosphorylation in the zebrafish rods and cones. Wada, Y., Sugiyama, J., Okano, T., Fukada, Y. J. Neurochem. (2006) [Pubmed]
  44. The cloning of GRK7, a candidate cone opsin kinase, from cone- and rod-dominant mammalian retinas. Weiss, E.R., Raman, D., Shirakawa, S., Ducceschi, M.H., Bertram, P.T., Wong, F., Kraft, T.W., Osawa, S. Mol. Vis. (1998) [Pubmed]
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