Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The defining characteristic of G protein-coupled receptor homologous desensitization is that the receptor must be occupied by an agonist or in an activated conformation that mimics an agonist-induced state. In most instances, the mechanistic basis for this characteristic is the high selectivity of G protein-coupled receptor kinases for the activated receptor. In this issue, Rankin et al. (p. 759) demonstrate that under some conditions, at least, the G protein-coupled receptor kinase GRK4 does not display a preference for the agonist-occupied D1 dopamine receptor. Coexpression of GRK4 and the D1 receptor in a heterologous system induces phosphorylation of the receptor in the absence of agonist, causing constitutive desensitization and internalization of the receptor. Lacking the normal rapid feedback mechanisms associated with homologous desensitization, a system incorporating constitutively active GRK4 will be prone to dysregulation, perhaps explaining the generally low expression of GRK4. 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).
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PMID:Novel features of G protein-coupled receptor kinase 4. 1633 88

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. The three GRK4 variants were genotyped by PCR-RFLP analysis. Both haplotype and single locus analysis were used to process the genotyping data. The A486 allele showed a significant association with HT (P < 0.001). A total of 6 haplotypes were observed in the entire population, with the haplotypes L-V-A and R-A-A being found to be significantly related to hypertension (P= 0.001).
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PMID:Association study of G protein-coupled receptor kinase 4 gene variants with essential hypertension in northern Han Chinese. 1704 52

During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and water and electrolyte balance by engendering natriuresis. Dopamine exerts its effects on dopamine receptors, including the dopamine D(3) receptor. G protein-coupled receptor kinase 4 (GRK4), whose gene locus (4p16.3) is linked to essential hypertension, desensitizes the D(1) receptor, another dopamine receptor. This study evaluated the role of GRK4 on D(3) receptor function in human proximal tubule cells. D(3) receptor co-segregated in lipid rafts and co-immunoprecipitated and co-localized in human proximal tubule cells and in proximal and distal tubules and glomeruli of kidneys of Wistar Kyoto rats. Bimolecular fluorescence complementation and confocal microscopy revealed that agonist activation of the receptor initiated the interaction between D(3) receptor and GRK4 at the cell membrane and promoted it intracellularly, presumably en route to endosomal trafficking. Of the four GRK4 splice variants, GRK4-gamma and GRK4-alpha mediated a 3- and 2-fold increase in the phosphorylation of agonist-activated D(3) receptor, respectively. 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. These data demonstrate that GRK4, specifically the GRK4-gamma and GRK4-alpha isoforms, phosphorylates the D(3) receptor and is crucial for its signaling in human proximal tubule cells.
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PMID:G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor. 1952 Aug 68