Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2008 Jun;51(6):1449-55.
doi: 10.1161/HYPERTENSIONAHA.107.096487. Epub 2008 Mar 17.

G protein-coupled receptor kinase 4: role in blood pressure regulation

Chunyu Zeng  1 , Van Anthony M Villar, Gilbert M Eisner, Scott M Williams, Robin A Felder, Pedro A Jose
Affiliations
Review

G protein-coupled receptor kinase 4: role in blood pressure regulation

Chunyu Zeng et al. Hypertension. 2008 Jun.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
GRK4 and D1R phosphorylation and dephosphorylation. Top, Schematic representation of the structure of GRK4 with its polymorphisms. The positions of the GRK4 gene variants associated with hypertension are shown in red. The numbers represent amino acid residues in GRK4. Bottom, Desensitization, which refers to the waning of the receptor’s responsiveness to further stimulation, involves several processes, including phosphorylation/modification, sequestration/internalization, and degradation of receptor protein.,–,,, The initial step in the desensitization process subsequent to ligand occupation of the receptor is the dissociation of the cognate trimeric G protein from the receptor followed by the phosphorylation or modification of the receptor by GRKs. The phosphorylation of GPCRs, including D1Rs, leads to the binding of members of the arrestin family and other proteins involved in the endocytic pathway. The internalized GPCRs meant for recycling to the cell membrane (CM) are dephosphorylated (resensitization) in endosomes via protein phosphatases, ie, PP2A in the case of the D1R.
Figure 2
Figure 2
Consequences of constitutive activation of GRK4γ variants expressed in renal proximal tubule and thick ascending limb of Henle. Constitutive activation of GRK4γ gene variants causes D1R phosphorylation or modification in the renal proximal tubule and thick ascending limb of Henle. The uncoupling of the D1R from its G protein– effector complex decreases D1R function and impairs its ability to decrease sodium transport. The increase in sodium balance increases endogenous ouabain, which inhibits Na+K+ ATPase activity, increasing intracellular calcium and vascular smooth muscle reactivity, augmenting the hypertension. GRK4 also affects other receptor genes. GRK4 gene variants increase AT1R expression and activity, contributing to the hypertension.
Figure 3
Figure 3
Meta-analyses of 3 GRK4 polymorphisms. A random-effect model used for meta-analysis (RevMan 4.2 software, http://www.cc-ims.net/RevMan) allows testing of the distribution of effects across different studies and provides wider confidence intervals when inconclusive data are present. Heterogeneity was tested using χ2 analysis, with P<0.1 considered as significant. We also report the I2 value, which estimates the proportion of total variation that is because of heterogeneity., An I2 value >50% was considered significant heterogeneity. Meta-analyses for R65L and A142V indicate that these variants, by themselves, are not associated with essential hypertension (not shown); meta-analysis for A486V indicates that 486V associates with essential hypertension.
See this image and copyright information in PMC

References

    1. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003;290:199–206. - PubMed
    1. Felder RA, Jose PA. Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity. Nat Clin Pract Nephrol. 2006;2:637–650. - PubMed
    1. Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med. 2002;34:88–95. - PubMed
    1. Nesbitt T, Coffman TM, Griffiths R, Drezner MK. Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest. 1992;89:1453–1459. - PMC - PubMed
    1. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481–490. - PubMed

Publication types

Substances