Cross talk between beta-adrenergic and bradykinin B-2 receptors results incooperative regulation of cyclic AMP accumulation and mitogen-activated protein kinase activity

Costimulation of G protein-coupled receptors (GPCRs) may result in cross ta lk interactions between their downstream signaling pathways. Stimulation of GPCRs may also lead to cross talk regulation of receptor tyrosine kinase s ignaling and thereby to activation of mitogen-activated protein kinase (MAP K). In COS-7 cells, we investigated the interactions between two particular mitogenic receptor pathways, the endogenously expressed beta -adrenergic r eceptor (P-AR) and the transiently transfected human bradykinin (BK) B. rec eptor (B2R). When beta -AR and B2R are costimulated, we found two different cross talk mechanisms. First, the predominantly G(q) protein-coupled B2R i s enabled to activate a G, protein and, subsequently, type II adenylate cyc lase. This results in augmentation of beta -AR-mediated cyclic AMP (cAMP) a ccumulation by BK, which alone is unable to increase the cAMP level. Second , independently of BK-induced superactivation of the cAMP system, costimula tion of beta -AR leads to protein kinase A-mediated blockade of phospholipa se C activation by BK. Thereby, the pathway from B2R to MAPK, which essenti ally involves protein kinase C activation, is selectively switched off. The MAPK activation in response to isoproterenol was not affected due to costi mulation. Furthermore, in the presence of isoproterenol, BK lost its abilit y to stimulate DNA synthesis in COS-7 cells. Thus, our findings might estab lish a novel paradigm: cooperation between simultaneously activated mitogen ic pathways may prevent multiple stimulation of MAPK activity and increased cell growth.