Alternative titles; symbols
HGNC Approved Gene Symbol: GRK5
Cytogenetic location: 10q26.11 Genomic coordinates (GRCh38): 10:119,207,571-119,459,745 (from NCBI)
G protein-coupled receptor (GPCR) kinases (GRKs), such as GRK5, are important regulators of GPCR function and mediate receptor desensitization, internalization, and signaling. Several non-GPCR proteins also serve as GRK substrates, and GRKs have been shown to have kinase-independent functions in receptor and effector regulation (summary by Michal et al., 2012).
By PCR on neutrophil cDNA using primers based on sequences of known receptor kinases, Haribabu and Snyderman (1993) identified GPRK5 and GPRK6 (GRK6; 600869) sequences.
Using degenerate oligonucleotide primers to amplify GRK-conserved sequences from a heart cDNA library, followed by screening the heart cDNA library, Kunapuli and Benovic (1993) cloned GRK5. The deduced 590-amino acid protein has a predicted central protein kinase catalytic domain and a calculated molecular mass of 67.7 kD. GRK5 shares 69% amino acid identity with IT11 (GRK4; 137026) and is also closely related to Drosophila Gprk2 and bovine rhodopsin kinase (GRK1; 180381). Northern blot analysis detected a GRK5 transcript of about 3 kb that showed highest expression in human heart, placenta, and lung, followed by skeletal muscle, brain, liver, and pancreas, with little expression in kidney.
By Western blot analysis and immunohistochemical analysis of human cell lines, Michal et al. (2012) showed that GRK5 colocalized with gamma-tubulin (see 191135), centrin (see 603187) and pericentrin (PCNT; 605925) at centrosomes and that it preferentially associated with the mother centriole. In synchronized HeLa cells, GRK5 associated with centrosomes predominantly during interphase and dispersed during mitosis.
Kunapuli and Benovic (1993) determined that the 5-prime UTR of GPRK5 is relatively GC rich.
Bullrich et al. (1995) used a rodent-human hybrid panel to map 2 newly identified members of the GRK family: GPRK5 and GPRK6 (600869) to 10q24-qter and 5q35, respectively. The hybrid cells containing parts of chromosomes 10 and 5 were used for the regionalization.
Kunapuli and Benovic (1993) showed that GRK5 expressed in insect cells phosphorylated rhodopsin (RHO; 180380) in a light-dependent manner.
Fan and Malik (2003) noted that desensitization of GPCRs regulates the number of polymorphonuclear leukocytes (PMNs), as well as their motility and ability to stop upon contact with pathogens or target cells, and this desensitization is mediated by GRKs. They found that MIP2 (CXCL2; 139110) induces GRK2 (109635) and GRK5 expression in PMNs through PI3KG (PIK3CG; 601232) signaling. However, lipopolysaccharide (LPS), acting through TLR4 (603030) signaling, mediated through MEK1 (176872)/MEK2 (601263), transcriptionally downregulates expression of GRK2 and GRK5 in response to MIP2, which decreases chemokine receptor desensitization and markedly augments PMN migration. Therefore, LPS-activated TLR4 signaling regulates PMN migration by modulating the expression of chemokine receptors in a GRK2- and GRK5-dependent manner.
By depolymerizing microtubules, Michal et al. (2012) showed that association of GRK5 with centrosomes in human cell lines was independent of microtubules. Knockdown of GRK5 expression in HeLa cells induced G2/M arrest or delay, which appeared to be due to increased expression of p53 (TP53; 191170), inhibition of AURKA (603072), and subsequent delay in PLK1 (602098) activation.
Liggett et al. (2008) identified a leu41-to-gln (L41Q) polymorphism in the GRK5 gene that was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. Studies in transfected cells and transgenic mice showed that GRK5-L41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Q41 and protected against experimental catecholamine-induced cardiomyopathy, similarly to pharmacologic beta-blockade. In 375 prospectively followed African American patients with heart failure, GRK5-L41 protected against death or cardiac transplantation. Liggett et al. (2008) concluded that enhanced beta-adrenergic receptor desensitization of excessive catecholamine signaling by GRK-L41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in that population.
By targeted deletion, Gainetdinov et al. (1999) created Grk5-null mice. Homozygous mutant mice were viable and showed no anatomic or behavioral abnormalities compared with wildtype littermates. However, the core body temperature of mutant mice was about 0.9 degrees C below normal. Since the central cholinergic system is involved in thermoregulation, Gainetdinov et al. (1999) challenged mutant mice with a nonselective muscarinic agonist, oxotremorine. Mutant mice showed enhanced classical cholinergic responses, such as hypothermia, hypoactivity, tremor, and salivation. The antinociceptive effect of oxotremorine was potentiated and prolonged, and muscarinic receptors in brains of Grk5-null mice resisted oxotremorine-induced desensitization.
Bullrich, F., Druck, T., Kunapuli, P., Gomez, J., Gripp, K. W., Schlegelberger, B., Lasota, J., Aronson, M., Cannizzaro, L. A., Huebner, K., Benovic, J. L. Chromosomal mapping of the genes GPRK5 and GPRK6 encoding G protein-coupled receptor kinases GRK5 and GRK6. Cytogenet. Cell Genet. 70: 250-254, 1995. [PubMed: 7789183] [Full Text: https://doi.org/10.1159/000134045]
Fan, J., Malik, A. B. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nature Med. 9: 315-321, 2003. Note: Erratum: Nature 9: 477 only, 2003. [PubMed: 12592402] [Full Text: https://doi.org/10.1038/nm832]
Gainetdinov, R. R., Bohn, L. M., Walker, J. K. L., Laporte, S. A., Macrae, A. D., Caron, M. G., Lefkowitz, R. J., Premont, R. T. Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron 24: 1029-1036, 1999. [PubMed: 10624964] [Full Text: https://doi.org/10.1016/s0896-6273(00)81048-x]
Haribabu, B., Snyderman, R. Identification of additional members of human G-protein-coupled receptor kinase multigene family. Proc. Nat. Acad. Sci. 90: 9398-9402, 1993. [PubMed: 8415712] [Full Text: https://doi.org/10.1073/pnas.90.20.9398]
Kunapuli, P., Benovic, J. L. Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family. Proc. Nat. Acad. Sci. 90: 5588-5592, 1993. [PubMed: 7685906] [Full Text: https://doi.org/10.1073/pnas.90.12.5588]
Liggett, S. B., Cresci, S., Kelly, R. J., Syed, F. M., Matkovich, S. J., Hahn, H. S., Diwan, A., Martini, J. S., Sparks, L., Parekh, R. R., Spertus, J. A., Koch, W. J., Kardia, S. L. R., Dorn, G. W., II. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nature Med. 14: 510-517, 2008. [PubMed: 18425130] [Full Text: https://doi.org/10.1038/nm1750]
Michal, A. M., So, C. H., Beeharry, N., Shankar, H., Mashayekhi, R., Yen, T. J., Benovic, J. L. G protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression. J. Biol. Chem. 287: 6928-6940, 2012. [PubMed: 22223642] [Full Text: https://doi.org/10.1074/jbc.M111.298034]