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Gene Review

GRK6  -  G protein-coupled receptor kinase 6

Homo sapiens

Synonyms: G protein-coupled receptor kinase GRK6, GPRK6
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Disease relevance of GRK6


High impact information on GRK6


Chemical compound and disease context of GRK6


Biological context of GRK6


Anatomical context of GRK6

  • RNA blot analysis of GRK6 with selected human tissues reveals two distinct mRNAs of 3 and 2.4 kilobases with a distribution very similar to that of beta ARK (i.e. brain, skeletal muscle > pancreas > heart, lung, kidney, placenta > liver) [7].
  • This activity increase by lipid modification is expected, as the lipid helps GRK6 localize to cellular membranes where its receptor substrates are found [9].
  • Moreover, GRK6 appears to be expressed at a much higher level in pregnant term tissue than in non-pregnant myometrium [10].
  • COS-7 cells were co-transfected with alpha2C10 or alpha2C4 without or with the following GRKs: betaARK, betaARK2, GRK5, or GRK6 [11].
  • These data demonstrate that betaARK and GRK6 expression are differentially regulated during myelomonocytic cell development and lymphocyte activation [5].

Associations of GRK6 with chemical compounds


Physical interactions of GRK6


Regulatory relationships of GRK6

  • The structure reveals a putative phospholipid-binding site near the N terminus of GRK6 and structural elements within the kinase substrate channel that likely influence G protein-coupled receptor access and specificity [17].

Other interactions of GRK6

  • Six GRK subtypes have so far been identified, named GRK1 to GRK6 [18].
  • Interestingly, similar regions in GRK4 and GRK6 appear to be palmitoylated (and involved in membrane interaction), suggesting evolutionary conservation of the function of this domain [19].
  • Rhodopsin and the beta 2-adrenergic and m2 muscarinic cholinergic receptors serve as stimulus-dependent substrates for GRK6, but with stoichiometries significantly lower than achieved by GRK5 and beta ARK [6].
  • Further, chemical depalmitoylation reduces the casein phosphorylation activity of the palmitoylated, but not prenylated, GRK6 kinase [9].
  • Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged [20].

Analytical, diagnostic and therapeutic context of GRK6


  1. Regulation of human melanocortin 1 receptor signaling and trafficking by thr-308 and ser-316 and its alteration in variant alleles associated with red hair and skin cancer. Sánchez-Laorden, B.L., Jiménez-Cervantes, C., García-Borrón, J.C. J. Biol. Chem. (2007) [Pubmed]
  2. Endogenous G protein-coupled receptor kinase 6 Regulates M3 muscarinic acetylcholine receptor phosphorylation and desensitization in human SH-SY5Y neuroblastoma cells. Willets, J.M., Challiss, R.A., Nahorski, S.R. J. Biol. Chem. (2002) [Pubmed]
  3. 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]
  4. 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]
  5. Differentially regulated expression of the G-protein-coupled receptor kinases, betaARK and GRK6, during myelomonocytic cell development in vitro. Loudon, R.P., Perussia, B., Benovic, J.L. Blood (1996) [Pubmed]
  6. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6. Loudon, R.P., Benovic, J.L. J. Biol. Chem. (1994) [Pubmed]
  7. Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family. Benovic, J.L., Gomez, J. J. Biol. Chem. (1993) [Pubmed]
  8. 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]
  9. Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6. Stoffel, R.H., Inglese, J., Macrae, A.D., Lefkowitz, R.J., Premont, R.T. Biochemistry (1998) [Pubmed]
  10. Expression of G-protein-coupled receptor kinases in pregnant term and non-pregnant human myometrium. Brenninkmeijer, C.B., Price, S.A., López Bernal, A., Phaneuf, S. J. Endocrinol. (1999) [Pubmed]
  11. 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]
  12. Effect of different G protein-coupled receptor kinases on phosphorylation and desensitization of the alpha1B-adrenergic receptor. Diviani, D., Lattion, A.L., Larbi, N., Kunapuli, P., Pronin, A., Benovic, J.L., Cotecchia, S. J. Biol. Chem. (1996) [Pubmed]
  13. Bimodal regulation of the human H1 histamine receptor by G protein-coupled receptor kinase 2. Iwata, K., Luo, J., Penn, R.B., Benovic, J.L. J. Biol. Chem. (2005) [Pubmed]
  14. Phosphorylation and desensitization of the human thromboxane receptor-alpha by G protein-coupled receptor kinases. Zhou, H., Yan, F., Tai, H.H. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  15. Cardiopulmonary bypass decreases G protein-coupled receptor kinase activity and expression in human peripheral blood mononuclear cells. Hagen, S.A., Kondyra, A.L., Grocott, H.P., El-Moalem, H., Bainbridge, D., Mathew, J.P., Newman, M.F., Reves, J.G., Schwinn, D.A., Kwatra, M.M. Anesthesiology (2003) [Pubmed]
  16. G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction. Hall, R.A., Spurney, R.F., Premont, R.T., Rahman, N., Blitzer, J.T., Pitcher, J.A., Lefkowitz, R.J. J. Biol. Chem. (1999) [Pubmed]
  17. The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs. Lodowski, D.T., Tesmer, V.M., Benovic, J.L., Tesmer, J.J. J. Biol. Chem. (2006) [Pubmed]
  18. Inhibition of G protein-coupled receptor kinase subtypes by Ca2+/calmodulin. Chuang, T.T., Paolucci, L., De Blasi, A. J. Biol. Chem. (1996) [Pubmed]
  19. 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]
  20. 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]
  21. Identification and chromosomal localization of a processed pseudogene of human GRK6. Gagnon, A.W., Benovic, J.L. Gene (1997) [Pubmed]
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