Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells

Hypertension is a multigenic disorder in which abnormal counterregulation between dopamine and Ang II plays a role. Recent studies suggest that this counterregulation results, at least in part, from regulation of the expression of both the antihypertensive dopamine 5 receptor (D(5)R) and the prohypertensive Ang II type 1 receptor (AT(1)R). in this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding D(5)R in mice increased both blood pressure and AT(1)R protein expression, and the increase in blood pressure was reversed by AT(1)R blockade. Activation of D(5)R increased the degradation of glycosylated AT(1)R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human AT(1)R and D(5)R. Confocal microscopy, Forster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of D(5)R initiated ubiquitination of the glycosylated AT,R at the plasma membrane. The regulated degradation of AT(1)R via a ubiquitin/proteasome pathway by activation of D(5)R provides what we believe to be a novel mechanism whereby blood pressure can be regulated by the interaction of 2 counterregulatory GPCRs. Our results therefore suggest that treatments for hypertension might be optimized by designing compounds that can target the AT(1)R and the D(5)R.