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H ypertension 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 (D₅R) and the prohypertensive Ang II type 1 receptor (AT₁R). In this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding D₅R in mice increased both blood pressure and AT₁R protein expression, and the increase in blood pressure was reversed by AT₁R blockade. Activation of D₅R increased the degradation of glycosylated AT₁R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human AT₁R and D₅R. Confocal microscopy, Förster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of D₅R initiated ubiquitination of the glycosylated AT₁R at the plasma membrane. The regulated degradation of AT₁R via a ubiquitin/proteasome pathway by activation of D₅R 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 AT₁R and the D₅R.