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Gene Review

GRK5  -  G protein-coupled receptor kinase 5

Homo sapiens

Synonyms: G protein-coupled receptor kinase GRK5, GPRK5
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Disease relevance of GRK5

  • GRK5, overexpressed in Sf9 insect cells using the baculovirus system, was able to phosphorylate rhodopsin in a light-dependent manner [1].
  • The results point to differences in which myocardial GRKs are regulated in cardiac disease, whereby changes in GRK2 expression may be related to the global effects of the disease on myocardial adrenoceptor function and those in GRK5 may be localized to the ventricles, depending on the nature of the myocardial load [2].
  • An inbred cardiomyopathic hamster strain, J2N-k, was used to investigate the alteration of GRK5 mRNA expression in the setting of congestive heart failure [3].
  • The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease [4].

High impact information on GRK5


Biological context of GRK5

  • Ca(2+)/CaM binding to the N-terminal CaM binding site of GRK5 mediates this effect [8].
  • Mutation of basic residues in the catalytic domain of GRK5 (between amino acids 388 and 395) results in the nuclear exclusion of the mutant enzyme (GRK5(Delta)(NLS)), demonstrating that GRK5 contains a functional NLS [8].
  • The ubiquitous calcium binding protein calmodulin (CaM) can inhibit GRK5 with a high affinity (IC50=40-50 nM) [9].
  • For example, GRK5 activity is strongly inhibited by protein kinase C phosphorylation and by Ca2+-calmodulin binding [10].
  • Heparin and dextran sulfate were found to be potent inhibitors of GRK5 with IC50 values of approximately 1 nM, thereby being at least 150-fold more potent on GRK5 than on beta ARK [11].

Anatomical context of GRK5


Associations of GRK5 with chemical compounds

  • Using glutathione S-transferase-GRK5 fusion proteins either to inhibit calmodulin-stimulated autophosphorylation or to bind directly to calmodulin, we determined that an amino-terminal domain of GRK5 (amino acids 20-39) is sufficient for calmodulin binding [15].
  • We find that lipopolysaccharide (LPS)-induced ERK1/2 phosphorylation is significantly enhanced in arrestin-2 and GRK5 knockdown cells [16].
  • GRK5 can also be activated by polycations, with 10 microM polylysine promoting an approximately 2.6-fold activation [11].
  • We report that membrane-bound hSPR is phosphorylated by purified GRK5, and that both the rate and extent of phosphorylation increase dramatically in the presence of substance P [17].
  • Epinephrine treatment for 1 min induced a rapid increase in the phosphorylation of the GRK5 and PKA- mutant betaARs as well as the WT [18].

Physical interactions of GRK5

  • Last, we show that mutation of the hydrophobic residues severely diminishes phospholipid-dependent autophosphorylation of GRK5 and phosphorylation of membrane-bound rhodopsin by GRK5 [19].

Enzymatic interactions of GRK5


Co-localisations of GRK5


Regulatory relationships of GRK5


Other interactions of GRK5


Analytical, diagnostic and therapeutic context of GRK5


  1. 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]
  2. 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]
  3. Enhanced GRK5 expression in the hearts of cardiomyopathic hamsters, J2N-k. Takagi, C., Urasawa, K., Yoshida, I., Takagi, Y., Kaneta, S., Nakano, N., Onozuka, H., Kitabatake, A. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  4. The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease. Arawaka, S., Wada, M., Goto, S., Karube, H., Sakamoto, M., Ren, C.H., Koyama, S., Nagasawa, H., Kimura, H., Kawanami, T., Kurita, K., Tajima, K., Daimon, M., Baba, M., Kido, T., Saino, S., Goto, K., Asao, H., Kitanaka, C., Takashita, E., Hongo, S., Nakamura, T., Kayama, T., Suzuki, Y., Kobayashi, K., Katagiri, T., Kurokawa, K., Kurimura, M., Toyoshima, I., Niizato, K., Tsuchiya, K., Iwatsubo, T., Muramatsu, M., Matsumine, H., Kato, T. J. Neurosci. (2006) [Pubmed]
  5. Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. Geras-Raaka, E., Arvanitakis, L., Bais, C., Cesarman, E., Mesri, E.A., Gershengorn, M.C. J. Exp. Med. (1998) [Pubmed]
  6. Susceptibility genes for age-related maculopathy on chromosome 10q26. Jakobsdottir, J., Conley, Y.P., Weeks, D.E., Mah, T.S., Ferrell, R.E., Gorin, M.B. Am. J. Hum. Genet. (2005) [Pubmed]
  7. G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells. Tiruppathi, C., Yan, W., Sandoval, R., Naqvi, T., Pronin, A.N., Benovic, J.L., Malik, A.B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. G protein-coupled receptor kinase 5 contains a DNA-binding nuclear localization sequence. Johnson, L.R., Scott, M.G., Pitcher, J.A. Mol. Cell. Biol. (2004) [Pubmed]
  9. Regulation of G-protein-coupled receptor kinase subtypes by calcium sensor proteins. Iacovelli, L., Sallese, M., Mariggiò, S., de Blasi, A. FASEB J. (1999) [Pubmed]
  10. Structure-function analysis of G protein-coupled receptor kinase-5. Role of the carboxyl terminus in kinase regulation. Pronin, A.N., Carman, C.V., Benovic, J.L. J. Biol. Chem. (1998) [Pubmed]
  11. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. Kunapuli, P., Onorato, J.J., Hosey, M.M., Benovic, J.L. J. Biol. Chem. (1994) [Pubmed]
  12. Involvement of G protein-coupled receptor kinase 5 in homologous desensitization of the thyrotropin receptor. Nagayama, Y., Tanaka, K., Hara, T., Namba, H., Yamashita, S., Taniyama, K., Niwa, M. J. Biol. Chem. (1996) [Pubmed]
  13. G protein-coupled receptor kinase specificity for phosphorylation and desensitization of alpha2-adrenergic receptor subtypes. Jewell-Motz, E.A., Liggett, S.B. J. Biol. Chem. (1996) [Pubmed]
  14. 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]
  15. Regulation of G protein-coupled receptor kinases by calmodulin and localization of the calmodulin binding domain. Pronin, A.N., Satpaev, D.K., Slepak, V.Z., Benovic, J.L. J. Biol. Chem. (1997) [Pubmed]
  16. Arrestin-2 and G Protein-coupled Receptor Kinase 5 Interact with NF{kappa}B1 p105 and Negatively Regulate Lipopolysaccharide-stimulated ERK1/2 Activation in Macrophages. Parameswaran, N., Pao, C.S., Leonhard, K.S., Kang, D.S., Kratz, M., Ley, S.C., Benovic, J.L. J. Biol. Chem. (2006) [Pubmed]
  17. Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in vitro. Warabi, K., Richardson, M.D., Barry, W.T., Yamaguchi, K., Roush, E.D., Nishimura, K., Kwatra, M.M. FEBS Lett. (2002) [Pubmed]
  18. Desensitization of beta2-adrenergic receptors with mutations of the proposed G protein-coupled receptor kinase phosphorylation sites. Seibold, A., January, B.G., Friedman, J., Hipkin, R.W., Clark, R.B. J. Biol. Chem. (1998) [Pubmed]
  19. A predicted amphipathic helix mediates plasma membrane localization of GRK5. Thiyagarajan, M.M., Stracquatanio, R.P., Pronin, A.N., Evanko, D.S., Benovic, J.L., Wedegaertner, P.B. J. Biol. Chem. (2004) [Pubmed]
  20. G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95. Hu, L.A., Chen, W., Premont, R.T., Cong, M., Lefkowitz, R.J. J. Biol. Chem. (2002) [Pubmed]
  21. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6. Loudon, R.P., Benovic, J.L. J. Biol. Chem. (1994) [Pubmed]
  22. Molecular pharmacology and modeling of vasopressin receptors. Thibonnier, M., Coles, P., Thibonnier, A., Shoham, M. Prog. Brain Res. (2002) [Pubmed]
  23. Development of a yeast bioassay to characterize G protein-coupled receptor kinases. Identification of an NH2-terminal region essential for receptor phosphorylation. Noble, B., Kallal, L.A., Pausch, M.H., Benovic, J.L. J. Biol. Chem. (2003) [Pubmed]
  24. Endosome sorting of beta 2-adrenoceptors is GRK5 independent. Millman, E.E., Rosenfeld, J.L., Vaughan, D.J., Nguyen, J., Dai, W., Alpizar-Foster, E., Clark, R.B., Knoll, B.J., Moore, R.H. Br. J. Pharmacol. (2004) [Pubmed]
  25. Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading. Hata, J.A., Williams, M.L., Schroder, J.N., Lima, B., Keys, J.R., Blaxall, B.C., Petrofski, J.A., Jakoi, A., Milano, C.A., Koch, W.J. J. Card. Fail. (2006) [Pubmed]
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