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 H-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,. 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). (C) 2009 Elsevier Inc. All rights reserved.