In different native tissues and cells the receptor for the vasodepressor bradykinin, B(2), forms dimers with the receptor for the vasopressor angiotensin II, AT(1). Because AT(1)/B(2) heterodimers may contribute to enhanced angiotensin II-stimulated signaling under pathophysiological conditions, we analyzed mechanisms of AT(1)/B(2) heterodimerization. We found that efficient B(2) receptor maturation was a prerequisite for heterodimerization because only the fully mature B(2) receptor was capable to interact with AT(1). To identify chaperones involved in B(2) receptor maturation and heterodimerization we performed microarray gene expression profiling of human embryonic kidney (HEK293) cells. The expression of the chaperone calreticulin was up-regulated in cells with efficient B(2) receptor maturation. Vice versa, upon down regulation of calreticulin expression by RNA interference, B(2) receptor maturation and AT(1)/B(2) receptor heterodimerization were significantly impaired. Concomitantly, the B(2) receptor-mediated enhancement of AT(1)-stimulated signaling was reduced. Thus, calreticulin enhances B(2) receptor maturation and heterodimerization with AT(1).
