Calreticulin enhances B2 bradykinin receptor maturation and heterodimerization

In different native tissues and cells the receptor for the vasodepressor bradykinin, B2, forms dimers with the receptor for the vasopressor angiotensin II, AT1. Because AT1/B2 heterodimers may contribute to enhanced angiotensin II-stimulated signaling under pathophysiological conditions, we analyzed mechanisms of AT1/B2 heterodimerization. We found that efficient B2 receptor maturation was a prerequisite for heterodimerization because only the fully mature B2 receptor was capable to interact with AT1. To identify chaperones involved in B2 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 B2 receptor maturation. Vice versa, upon down regulation of calreticulin expression by RNA interference, B2 receptor maturation and AT1/B2 receptor heterodimerization were significantly impaired. Concomitantly, the B2 receptor-mediated enhancement of AT1-stimulated signaling was reduced. Thus, calreticulin enhances B2 receptor maturation and heterodimerization with AT1.