Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension

Abstract

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. D₁-like receptors (D₁R and D₅R) stimulate, while D2-like receptors (D₂R, D₃R, and D₄R) 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 D₁R and D₃R and their interaction in the natriuresis associated with volume expansion. The D₁R- and D₃R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D₃R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D₁R and D₃R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D₁R and D₃R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.

Keywords: D1R; D3R; G protein-coupled receptor kinase 4; dopamine receptor; hypertension.

Figure 1

The D₃R, GRK4, NHE3, and USP48 in human renal proximal tubule cells in the basal state (A) form a cohesive signaling network capable of selective GPCR activation and efficient signal propagation and amplification to target specific effector systems. D₃R stimulation (B) causes the: (1) inhibition of the activity of membrane-bound NHE3, via PLC/ PKC and via protein-protein interaction that results in the internalization, ubiquitinylation (aka ubiquitination) and trafficking of NHE3 into sorting endosomes, to late endosomes, and eventually into proteasomes where it is degraded; and (2) inhibition of the activity of internalized and cytoplasmic USP48. The agonist-occupied D₃R, homologously desensitized by GRK4γ and to a lesser extent, by GRK4α, is internalized and directed to the late recycling endosome dephosphorylated and re-inserted to the plasma membrane (PM). Not shown are the constitutively active GRK4γ variants (eg, GRK4γ 124V) which impair D₃R function, resulting in increased expression and activity of NHE3 (and other Na⁺ transporters), increased renal Na⁺ transport and balance, and increased blood pressure (hypertension).