Next Article in Journal
Anti-TMV Activity of Malformin A1, a Cyclic Penta-Peptide Produced by an Endophytic Fungus Aspergillus tubingensis FJBJ11
Next Article in Special Issue
Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response
Previous Article in Journal
Genome-Wide Identification and Analysis of Drought-Responsive Genes and MicroRNAs in Tobacco
Previous Article in Special Issue
β-Hydroxybutyric Sodium Salt Inhibition of Growth Hormone and Prolactin Secretion via the cAMP/PKA/CREB and AMPK Signaling Pathways in Dairy Cow Anterior Pituitary Cells
Open AccessReview

The Importance of G Protein-Coupled Receptor Kinase 4 (GRK4) in Pathogenesis of Salt Sensitivity, Salt Sensitive Hypertension and Response to Antihypertensive Treatment

by Brian Rayner 1,* and Raj Ramesar 2
Division of Nephrology and Hypertension, University of Cape Town, Cape Town 7925, South Africa
MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
Author to whom correspondence should be addressed.
Academic Editor: Kathleen Van Craenenbroeck
Int. J. Mol. Sci. 2015, 16(3), 5741-5749;
Received: 30 October 2014 / Revised: 6 January 2015 / Accepted: 15 January 2015 / Published: 12 March 2015
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
Salt sensitivity is probably caused by either a hereditary or acquired defect of salt excretion by the kidney, and it is reasonable to consider that this is the basis for differences in hypertension between black and white people. Dopamine acts in an autocrine/paracrine fashion to promote natriuresis in the proximal tubule and thick ascending loop of Henle. G-protein receptor kinases (or GRKs) are serine and threonine kinases that phosphorylate G protein-coupled receptors in response to agonist stimulation and uncouple the dopamine receptor from its G protein. This results in a desensitisation process that protects the cell from repeated agonist exposure. GRK4 activity is increased in spontaneously hypertensive rats, and infusion of GRK4 antisense oligonucleotides attenuates the increase in blood pressure (BP). This functional defect is replicated in the proximal tubule by expression of GRK4 variants namely p.Arg65Leu, p.Ala142Val and p.Val486Ala, in cell lines, with the p.Ala142Val showing the most activity. In humans, GRK4 polymorphisms were shown to be associated with essential hypertension in Australia, BP regulation in young adults, low renin hypertension in Japan and impaired stress-induced Na excretion in normotensive black men. In South Africa, GRK4 polymorphisms are more common in people of African descent, associated with impaired Na excretion in normotensive African people, and predict blood pressure response to Na restriction in African patients with mild to moderate essential hypertension. The therapeutic importance of the GRK4 single nucleotide polymorphisms (SNPs) was emphasised in the African American Study of Kidney Disease (AASK) where African-Americans with hypertensive nephrosclerosis were randomised to receive amlodipine, ramipril or metoprolol. Men with the p.Ala142Val genotype were less likely to respond to metoprolol, especially if they also had the p.Arg65Leu variant. Furthermore, in the analysis of response to treatment in two major hypertension studies, the 65Leu/142Val heterozygote predicted a significantly decreased response to atenolol treatment, and the 65Leu/142Val heterozygote and 486Val homozygote were associated in an additive fashion with adverse cardiovascular outcomes, independent of BP. In conclusion, there is considerable evidence that GRK4 variants are linked to impaired Na excretion, hypertension in animal models and humans, therapeutic response to dietary Na restriction and response to antihypertensive drugs. It may also underlie the difference in hypertension between different geographically derived population groups, and form a basis for pharmacogenomic approaches to treatment of hypertension. View Full-Text
Keywords: salt sensitivity; GRK4; ethnicity salt sensitivity; GRK4; ethnicity
Show Figures

Figure 1

MDPI and ACS Style

Rayner, B.; Ramesar, R. The Importance of G Protein-Coupled Receptor Kinase 4 (GRK4) in Pathogenesis of Salt Sensitivity, Salt Sensitive Hypertension and Response to Antihypertensive Treatment. Int. J. Mol. Sci. 2015, 16, 5741-5749.

Show more citation formats Show less citations formats

Article Access Map by Country/Region

Only visits after 24 November 2015 are recorded.
Back to TopTop