Disease relevance of GRK4

• Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension [1].
• Nonoverlapping fragments of this insert were used as probes and showed strong hybridization to a number of Mycobacterium tuberculosis-lambda gt11 recombinants producing proteins recognized by an anti-M. tuberculosis 71-kDa monoclonal antibody, IT11 [2].

High impact information on GRK4

• Surprisingly, this desensitization occurred in the absence of ligand-induced receptor phosphorylation and could be promoted by GRK4 mutants deleted of their kinase domain [3].
• Reciprocally, transfection of GRK4 in HEK293 cells restored agonist-promoted desensitization, confirming that this kinase is sufficient to support desensitization [3].
• Taking advantage of this cell-specific desensitization phenotype, we identified GRK4 as the kinase involved in the neuronal desensitization [3].
• G protein-coupled receptor kinase 4 gene variants in human essential hypertension [4].
• These results suggest that the GRK4 subfamily of GRKs may play a signaling role in the nucleus and that GRK4 and GRK2 subfamily members perform divergent cellular functions [5].

Biological context of GRK4

• The human GRK4 gene is composed of 16 exons extending over 75 kilobase pairs of DNA [6].
• This domain is abundant in basic and hydrophobic residues, characteristics typical of calmodulin binding sites, and is highly conserved in GRK4, GRK5, and GRK6 [7].
• G protein-coupled receptor kinase 4 (GRK4) presents some peculiar characteristics that make it a unique member within the GRK multigene family [8].
• The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation [9].
• Indeed, considerable evidence suggests that just such dysregulation resulting from mutationally activated GRK4 contributes to the heritable component of human essential hypertension (Physiol Genomics 19:223-246, 2004) [10].

Anatomical context of GRK4

• Human GRK4 mRNA is expressed highly only in testis, and both alternative exons are abundant in testis mRNA [6].
• Specific GRK4 immunoreactivity was only found on sperm membranes, and immunochemical and ultrastructural analyses showed that it is associated to the acrosomal membranes and to the outer mitochondrial membranes [8].
• A substantial expression of GRK4 mRNA was only found in testis and in the spermatogonia cell line GC-1 spg [8].
• In cells transfected with GRK4 and exposed to agonist, beta-arrestin was first recruited to plasma membranes, where it was co-localized with the mGlu(1) receptor, and then internalized in vesicles [11].
• Western blots of human kidney 293 cells (the cell line used in transfection experiments) and MSC-1 cells (a cell line derived from Sertoli cells that displays many of the differentiated functions of their normal counterparts) reveal the presence of GRK2 and GRK6 in both cell lines as well as GRK4 in MSC-1 cells [12].

Associations of GRK4 with chemical compounds

• GRK4 is capable of augmenting the desensitization of the rat luteinizing hormone/chorionic gonadotropin receptor upon coexpression in HEK293 cells and of phosphorylating the agonist-occupied, purified beta2-adrenergic receptor, indicating that GRK4 is a functional protein kinase [6].
• To determine whether the GRK4 genotype is associated with impaired D1R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n = 18) [13].
• SUMMARY: GRK4 single nucleotide polymorphisms, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic function of angiotensin II type 1 receptors to predominate, may be responsible for salt sensitivity [14].
• Role of G protein-coupled receptor kinase 4 and beta-arrestin 1 in agonist-stimulated metabotropic glutamate receptor 1 internalization and activation of mitogen-activated protein kinases [11].
• The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4 [15].
• Inhibition of GRK activity with heparin or knockdown of GRK4 expression via RNA interference completely abolished p44/42 phosphorylation and mitogenesis induced by D(3) receptor stimulation [16].

Other interactions of GRK4

• 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 [17].
• The genomic organization of the GRK4 gene is completely distinct from that of the human GRK2 gene, highlighting the evolutionary distance since the divergence of these two genes [6].
• Antibodies to GRK2, GRK3 and GRK4 were used to confirm the presence of the protein product in the human urinary bladder using immunohistochemical staining and the western blotting technique [18].
• Using PCR we found that G protein-coupled receptor kinase4 (GRK4) mRNA is expressed only in brain out of several tissues tested [19].
• Phosphatidylinositol-binding sequences more distantly related to HIKE are present in gelsolin, in the G protein-coupled receptor kinase 4 and in Trop-2 [20].

Analytical, diagnostic and therapeutic context of GRK4

• Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning [19].
• To investigate the association between polymorphisms in the G protein-coupled receptor kinase 4 gene (GRK4) (R65L, A142V and A486V) and essential hypertension in northern Han Chinese, we conducted a case-control study consisting of 503 individuals with essential hypertension (HT) and 490 age-, gender-, and area-matched normotensive (NT) controls [21].

References