Losartan binding to angiotensin AT1 receptors confers allosteric modification of dopamine D1 receptors

AT1R and D1R form a heteromeric‐signaling complex (Kahn et al. 2008). Here we test whether AT1R bound to losartan, an antagonist, might allosterically modulate D1R signaling. Co‐immunoprecipitation studies on rat proximal tubule cells (RPTC) showed that AT1R and D1R interaction was significantly strengthened after losartan preincubation. Biotinylation and cell image studies showed that losartan significantly increased the D1R plasma membrane expression. D1R is positively and AT1R is negatively coupled to adenylate cyclase. Losartan increased cAMP generation in RPTC. To test if this is due to D1R activation, we used HEK cells, that express low or non‐detectable AT1R and D1R levels. Losartan increased cAMP in cells transfected with both receptors but not in cells transfected with either receptor alone. We identified two amino acids (S397 and S398) in the D1R C‐terminus as binding motif for AT1R. Losartan had no effect on cAMP in cells transfected with AT1R and mutant D1R (S397A, S398 A). These data indicate that losartan, widely used as antihypertensive drug, exerts its effect by lowering angiotensin and enhancing dopamine tonus. As proof of principle, we showed that in rats with renal hypertension one week treatment with losartan alone had a significantly more pronounced antihypertensive effect than treatment with losartan and a D1 antagonist. Swedish Research Council and Heart lung foundation