Dopamine Receptor DR and DR and GRK4 Interaction in Hypertension

Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D-like receptors (DR and DR) stimulate, while D2-like receptors (DR, DR, and DR) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the DR and DR and their interaction in the natriuresis associated with volume expansion. The DR- and DR-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The DR also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of and in mice causes hypertension, polymorphisms are not always associated with human essential hypertension and polymorphisms in are not associated with human essential hypertension. The impaired DR and DR function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize DR and DR. The locus is linked to and variants are associated with high blood pressure in humans. Thus, , by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.