Alternative titles; symbols
HGNC Approved Gene Symbol: GRK6
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:177,425,523-177,442,891 (from NCBI)
By PCR on neutrophil cDNA using primers based on sequences of known receptor kinases, Haribabu and Snyderman (1993) identified GPRK5 (600870) and GPRK6 sequences. Using a fragment of the GPRK6 PCR clone to screen a cDNA library, they isolated a cDNA encoding GPRK6. Sequence analysis predicted that the 544-amino acid GPRK6 protein contains the conserved DLG (asp-leu-gly) and ENIL (glu-asn-ile-leu) motifs. Northern blot analysis detected 2.1- and 2.9-kb GPRK6 transcripts in all tissues tested, with strongest expression in placenta and skeletal muscle.
By screening a heart cDNA with the catalytic domains of BARK (ADRBK1; 109635), Benovic and Gomez (1993) isolated a cDNA encoding GRK6. The 576-amino acid GRK6 protein is 70% identical to GRK5. PAGE analysis showed expression of a 66-kD protein from an insect cell line.
Benovic and Gomez (1993) found that GRK6 could phosphorylate rhodopsin (RHO; 180380) in a light-dependent manner and ADRB2 (109690) in an agonist-dependent manner. However, GRK6 was significantly less active than BARK or GRK5 on these substrates.
Gaudreau et al. (2002) identified the leukotriene B4 receptor, BLT1 (LTB4R; 601531), as a substrate for GRK6. Thr308 in the BLT1 cytoplasmic tail was critical for inositol phosphate production and GRK6-mediated phosphorylation and desensitization of BLT1 signaling.
By somatic cell hybrid analysis, Haribabu and Snyderman (1993) mapped the GPRK6 gene and a closely related gene to chromosomes 5 and 13, respectively. Bullrich et al. (1995) mapped GPRK6 to 5q35 by analysis of a rodent human hybrid panel. The GPRK6-related locus was found to map to 13pter-q21.
Gainetdinov et al. (2003) noted that some GRKs have been shown to phosphorylate G protein-coupled dopamine receptors, thereby regulating their activity and mediating desensitization of the receptors. Using immunohistochemistry, Gainetdinov et al. (2003) found that GRK6 is expressed in striatal neurons receiving dopaminergic input, and that postsynaptic D2/D3 dopamine receptors are physiologic targets of this kinase. GRK6 knockout mice showed supersensitivity to the locomotor-stimulating effects of psychostimulants, including cocaine and amphetamine. In addition, these mice demonstrated an enhanced coupling of striatal D2-like dopamine receptors to G proteins and augmented response to direct dopamine agonists. Gainetdinov et al. (2003) noted that supersensitivity of dopamine signaling has been postulated to be involved in several brain disorders, including addiction.
Kavelaars et al. (2003) found that application of arachidonic acid to the ears of Grk6 -/- mice induced significantly increased inflammatory responses compared with wildtype mice. Neutrophils from Grk6 -/- mice responded to leukotriene B4 with a prolonged increase in intracellular calcium and actin polymerization. Kavelaars et al. (2003) concluded that GRK6 deficiency leads to prolonged BLT1 signaling and increased neutrophil migration.
Benovic, J. L., Gomez, J. Molecular cloning and expression of GRK6: a new member of the G protein-coupled receptor kinase family. J. Biol. Chem. 268: 19521-19527, 1993. [PubMed: 8366096]
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]
Gainetdinov, R. R., Bohn, L. M., Sotnikova, T. D., Cyr, M., Laakso, A., Macrae, A. D., Torres, G. E., Kim, K.-M., Lefkowitz, R. J., Caron, M. G., Premont, R. T. Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron 38: 291-303, 2003. [PubMed: 12718862] [Full Text: https://doi.org/10.1016/s0896-6273(03)00192-2]
Gaudreau, R., Le Gouill, C., Venne, M. H., Stankova, J., Rola-Pleszczynski, M. Threonine 308 within a putative casein kinase 2 site of the cytoplasmic tail of leukotriene B(4) receptor (BLT1) is crucial for ligand-induced, G-protein-coupled receptor-specific kinase 6-mediated desensitization. J. Biol. Chem. 277: 31567-31576, 2002. [PubMed: 12077128] [Full Text: https://doi.org/10.1074/jbc.M202723200]
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]
Kavelaars, A., Vroon, A., Raatgever, R. P., Fong, A. M., Premont, R. T., Patel, D. D., Lefkowitz, R. J., Heijnen, C. J. Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6. J. Immun. 171: 6128-6134, 2003. [PubMed: 14634128] [Full Text: https://doi.org/10.4049/jimmunol.171.11.6128]