RKIP enhances angiotensin II-stimulated signaling

Protein kinase C-mediated phosphorylation converts the raf kinase inhibitor protein (RKIP) into an inhibitor of the G protein-coupled receptor kinase 2 (GRK2). As a result of GRK2 inhibition, RKIP prevents receptor desensitization and enhances signaling stimulated by the classical substrate of GRK2, i.e., the Gscoupled b-adrenergic receptor. The Gq/11-coupled angiotensin II AT1 receptor is another prototypic substrate of GRK2 in the cardiovascular system. However, the role of RKIP in Gq/11-coupled receptor signaling is not clear. Here, we show that overexpression of RKIP in kidney cells led to a significant increase of the AT1-stimulated calcium signal. In contrast, a phosphorylation-deficient mutant of RKIP that cannot act as GRK2 inhibitor had no effect. Analogously to the signal sensitization of kidney cells, RKIP increased the angiotensin II-stimulated hypertrophic response of cardiomyocytes. RNA interference studies revealed that endogenous RKIP levels of kidney cells and cardiomyocytes were sufficient to produce signal enhancement of AT 1. Thus, RKIP acts as a physiological enhancer of angiotensin II-stimulated signaling in kidney cells and cardiomyocytes. © 2011 by Begell House, Inc.