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Gene Review

Grk4  -  G protein-coupled receptor kinase 4

Mus musculus

Synonyms: A830025H08Rik, G protein-coupled receptor kinase GRK4, GRK, Gprk2l, Gprk4
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Disease relevance of Gprk2l

  • These genetic approaches or the development of small molecule inhibitors of betaARK1 and GRK activity may advance therapeutic options for heart disease [1].

High impact information on Gprk2l

  • Here, we establish that GRK/beta-arrestin-mediated signal transduction via the angiotensin II (ANG) type 1A receptor (AT(1A)R) results in positive inotropic and lusitropic effects in isolated adult mouse cardiomyocytes [2].
  • METHODS AND RESULTS: Long-term in vivo stimulation of betaARs results in the impairment of cardiac +betaAR signaling and increases the level of expression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium [3].
  • Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to betaAR signaling [3].
  • Characterization of the mouse GRK 5 and 6 genes reveals that all members of the GRK4 subfamily share an identical gene structure, in which 15 introns interrupt the coding sequence at equivalent positions in all three genes [4].
  • GRK-mediated receptor phosphorylation facilitates the binding of an inhibitory arrestin protein to the phosphorylated receptor, an event which substantially impairs receptor signaling [5].

Biological context of Gprk2l

  • Involvement of G protein-coupled receptor kinase (GRK) 3 and GRK2 in down-regulation of the alpha2B-adrenoceptor [6].
  • Here, we have analyzed the expression of GRK2, the predominant GRK expressed during embryogenesis [7].
  • From current studies, it is known that various phosphorylation steps, such as protein kinase C (PKC) and G protein-coupled receptor (GPCR) kinase (GRK) regulate endocytosis [8].
  • The ability to manipulate the mouse genome has provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart [1].
  • Our observations argue that GRK1 is essential for normal deactivation of murine cone phototransduction and provide the first functional evidence for a major role of a specific GRK in the inactivation of vertebrate cone phototransduction [9].

Anatomical context of Gprk2l

  • In wild-type mice, chronic Delta9-tetrahydrocannabinol (THC) exposure significantly activated specific GRK and beta- arrestin subunits in all the considered brain areas (striatum, cerebellum, hippocampus, and prefrontal cortex), suggesting their involvement in the adaptive processes underlying CB1 receptor downregulation and desensitization [10].

Analytical, diagnostic and therapeutic context of Gprk2l


  1. Transgenic mice targeting the heart unveil G protein-coupled receptor kinases as therapeutic targets. Iaccarino, G., Koch, W.J. Assay and drug development technologies. (2003) [Pubmed]
  2. beta-Arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Rajagopal, K., Whalen, E.J., Violin, J.D., Stiber, J.A., Rosenberg, P.B., Premont, R.T., Coffman, T.M., Rockman, H.A., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Iaccarino, G., Tomhave, E.D., Lefkowitz, R.J., Koch, W.J. Circulation (1998) [Pubmed]
  4. The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation. Premont, R.T., Macrae, A.D., Aparicio, S.A., Kendall, H.E., Welch, J.E., Lefkowitz, R.J. J. Biol. Chem. (1999) [Pubmed]
  5. Desensitization of G protein-coupled receptors. Freedman, N.J., Lefkowitz, R.J. Recent Prog. Horm. Res. (1996) [Pubmed]
  6. Involvement of G protein-coupled receptor kinase (GRK) 3 and GRK2 in down-regulation of the alpha2B-adrenoceptor. Desai, A.N., Salim, S., Standifer, K.M., Eikenburg, D.C. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  7. Expression of the G protein-coupled receptor kinase 2 during early mouse embryogenesis. Sefton, M., Blanco, M.J., Penela, P., Mayor, F., Nieto, M.A. Mech. Dev. (2000) [Pubmed]
  8. Locus-specific involvement of anti-opioid systems in morphine tolerance and dependence. Ueda, H. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  9. Mice lacking G-protein receptor kinase 1 have profoundly slowed recovery of cone-driven retinal responses. Lyubarsky, A.L., Chen, C., Simon, M.I., Pugh, E.N. J. Neurosci. (2000) [Pubmed]
  10. Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade. Rubino, T., Viganò, D., Premoli, F., Castiglioni, C., Bianchessi, S., Zippel, R., Parolaro, D. Mol. Neurobiol. (2006) [Pubmed]
  11. Therapeutic potential of G-protein coupled receptor kinases in the heart. Iaccarino, G., Koch, W.J. Expert opinion on investigational drugs. (1999) [Pubmed]
  12. Cardiac betaARK1 upregulation induced by chronic salt deprivation in rats. Iaccarino, G., Barbato, E., Cipolleta, E., Esposito, A., Fiorillo, A., Koch, W.J., Trimarco, B. Hypertension (2001) [Pubmed]
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