Disease relevance of GRK1

• The relationship between myocardial G protein receptor kinase (GRK) expression and beta-adrenoceptor signalling in human left heart diseases has not been fully elucidated yet [1].
• G-protein-coupled receptor kinase activity is increased in hypertension [2].
• To date, three different mutations in the RK locus have been associated with Oguchi disease, an autosomal recessive form of stationary night blindness in man characterized in part by delayed photoreceptor recovery [Yamamoto, S. , Sippel, K. C., Berson, E. L. & Dryja, T. P. (1997) Nat. Genet. 15, 175-178] [3].
• Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants [4].
• The GRK and PKA site antibodies were also effective in detecting phosphorylation of the endogenous beta2AR expressed in A431 human epidermoid carcinoma cells [5].

Psychiatry related information on GRK1

• Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed [6].
• We suggest that high expression of RhoA contributes, through RhoA-mediated Ca(2+) sensitization, to the flaccid state of CC that can be reversed by a water-soluble, orally active Rho kinase inhibitor suitable for therapy of erectile dysfunction [7].
• G-protein coupled receptor supersensitivity, possibly as a result of decreased GRK, has been suggested in affective disorders [8].

High impact information on GRK1

• Our results identify a new role for PDZ-domain-mediated protein interactions and for the actin cytoskeleton in endocytic sorting, and suggest a mechanism by which GRK-mediated phosphorylation could regulate membrane trafficking of G-protein-coupled receptors after endocytosis [9].
• We show that overexpression of rhodopsin kinase (GRK1) increases phosphorylation of the GPCR rhodopsin but has no effect on photoresponse recovery [10].
• Here we investigate whether GRK or RGS governs the overall rate of recovery of the light response in mammalian rod photoreceptors, a model system for studying GPCR signaling [10].
• In cone-dominant animals as well as in humans, but not in rodents, GRK7, a cone-specific homolog of GRK1, has been identified in cone outer segments [11].
• Phosphorylation of rhodopsin by rhodopsin kinase GRK1 is an important desensitization mechanism in scotopic vision [11].

Chemical compound and disease context of GRK1

• Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation [4].
• Pretreatment of ganglion cell axons with C3-transferase, a specific inhibitor of the Rho GTPase, or with Y-27632, a specific inhibitor of the Rho kinase, strongly reduced the collapse rate of retinal growth cones [12].
• The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase [13].
• All of these LPS effects could be blocked by the Rho-GTPase inhibitor C3 transferase from Clostridium botulinum or the Rho kinase inhibitor Y-27632 [14].
• Induced barrier permeability is likely to be Galpha(12/13)-mediated as chelation of Galpha(q)-mediated intracellular calcium with BAPTA-AM, pertussis toxin inhibition of Galpha(i/o), or GM6001 inhibition of matrix metalloproteinase had no effect, whereas Y-27632 inhibition of the Galpha(12/13)-mediated Rho kinase abrogated the response [15].

Biological context of GRK1

• Human photoreceptors also transcribe a splice variant of GRK1, which differs in its C-terminal region next to the catalytic domain [16].
• Among these enzymes, GRK1 (rhodopsin kinase) is involved in phototransduction and is the most specialized of the family [16].
• Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient [17].
• It remains unclear why the loss of GRK1 yields such different phenotypes in the recovery of mouse and human cones [18].
• The disease in the Pakistani family localizes to 13q34 and is caused by a novel deletion including Exon 3 of the GRK1 gene [19].

Anatomical context of GRK1

• Thus, these studies suggest that rods and cones, express the same form of GRK1 [16].
• Based on results of molecular cloning and immunolocalization, it appears that both rod and cone photoreceptors express GRK1 [16].
• This novel variant, GRK1b, is produced by retention of the last intron. mRNA encoding GRK1b is exported to the cytosol; however, the level of the protein is relatively low compared with GRK1 (now called GRK1a), and GRK1b appears to have very low catalytic activity [16].
• Rod outer segments isolated from bovine retina phosphorylated the FLAG-tagged GRKs in the presence of dibutyryl-cAMP, suggesting that GRK1 and GRK7 are physiologically relevant substrates [20].
• These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects [2].

Associations of GRK1 with chemical compounds

• G protein-coupled receptor kinase-mediated desensitization of metabotropic glutamate receptor 1A protects against cell death [21].
• These studies suggest that CSP act as functional analogues in mediating the regulation of different GRK subtypes by Ca(2+) [22].
• Proline 391 is not only within the functionally important catalytic domain, but is also a phylogenetically conserved amino acid residue among GRK1 orthologs and homologs [23].
• The ability of these reagents to inhibit GRK- mediated receptor phosphorylation is demonstrated in permeabilized 293 cells that overexpress individual GRKs and the type 1A angiotensin II receptor [24].
• In this human in vivo condition without a functional RK and probable lack of phosphorylation and arrestin binding to activated rhodopsin, reduction of photolyzed chromophore and regeneration processes with 11-cis-retinal probably constitute the sole pathway for recovery of rod sensitivity [25].

Physical interactions of GRK1

• These results suggest that autophosphorylation plays an important role in regulating the binding of RK to Rho and that the binding sites of RK and arrestin overlap at least partially [26].
• Our analyses confirmed that Ca2+ is required for recoverin to bind RK [27].
• These observations represent the first demonstration of a mutant G protein-coupled receptor that assumes a conformation able to interact with its G protein-coupled receptor kinase and arrestin, but not with its G protein, in the absence of ligand [28].
• PIX is a Rac GTP exchange factor that also binds the G-protein-coupled receptor kinase-interacting protein known as GIT1 [29].

Enzymatic interactions of GRK1

• GRK1 phosphorylates photoactivated rhodopsin, initiating steps in its deactivation [16].
• Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration [30].
• Moreover, multiple members of the GRK family are able to phosphorylate the beta(2)AR and induce beta-arrestin recruitment, with their relative contributions largely determined by their relative expression levels [31].
• Functional significance of the specific sites phosphorylated in desmin at cleavage furrow: Aurora-B may phosphorylate and regulate type III intermediate filaments during cytokinesis coordinatedly with Rho-kinase [32].
• Recently, we have demonstrated that MARCKS is phosphorylated at Ser159 in PSD by Rho-kinase in vitro and that the phosphorylation occurred in neuronal cells upon stimulation with lysophosphatidic acid (LPA), and its phosphorylation was inhibited by a novel and specific Rho-kinase inhibitor, H-1152 [33].

Regulatory relationships of GRK1

• Rhodopsin kinase (GRK1) requires a post-translationally added farnesyl isoprenoid to bind to light-activated rhodopsin [34].
• The experiments presented herein were designed to identify members of the G protein-coupled receptor kinase (GRK) family that participate in the agonist-induced phosphorylation and internalization of the rat FSH receptor (rFSHR) [35].
• To test whether Hsp90 plays a general role in regulating GRK maturation, additional GRKs were studied by transient expression in COS-1 cells and subsequent treatment with geldanamycin [36].
• We conclude that both the ETA-R and ETB-R can be regulated indistinguishably by GRK-initiated desensitization [37].
• G protein-coupled receptor kinase-mediated receptor phosphorylation promotes the binding of beta-arrestin proteins, which not only uncouple GPCRs from their cognate heterotrimeric G protein, but also target them for endocytosis [38].

Other interactions of GRK1

• We isolated cDNAs corresponding to GPRK6; the complete sequence shows > 66% identity and 81% similarity at the amino acid level to the GPRK from the Huntington disease locus [39].
• Cloning and expression of GRK5: a member of the G protein-coupled receptor kinase family [40].
• Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor [41].
• CONCLUSIONS: The cone-dominant human retina resulting from NR2E3 mutations affords greater understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors [17].
• However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation [42].

Analytical, diagnostic and therapeutic context of GRK1

• Immunocytochemistry was performed with antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue [17].
• Genomic Southern blot analysis and chromosome mapping showed that GPRK6 hybridizes to two closely related genes located on chromosomes 5 and 13 and are, therefore, distinct from the GPRK located near the Huntington disease locus on chromosome 4 [39].
• To understand the molecular basis for these characteristics of cone responses, we focused on the opsin deactivation process initiated by G protein-coupled receptor kinase (GRK) 1 and GRK7 in the zebrafish, an animal model suitable for studies on retinal physiology and biochemistry [43].
• METHODS: RNA prepared from the retinas of two cone-dominant mammals, the thirteen-lined ground squirrel and the eastern chipmunk, and a rod-dominant mammal, the pig, was used to clone a new GRK family member by RT-PCR [44].
• Both a homozygote and heterozygote with this RK mutation had recovery phase abnormalities of rod-isolated photoresponses by electroretinography (ERG); photoactivation was normal [25].

References