Cross Talk between β-Adrenergic and Bradykinin B₂Receptors Results in Cooperative Regulation of Cyclic AMP Accumulation and Mitogen-Activated Protein Kinase Activity

Abstract

Costimulation of G protein-coupled receptors (GPCRs) may result in cross talk interactions between their downstream signaling pathways. Stimulation of GPCRs may also lead to cross talk regulation of receptor tyrosine kinase signaling and thereby to activation of mitogen-activated protein kinase (MAPK). In COS-7 cells, we investigated the interactions between two particular mitogenic receptor pathways, the endogenously expressed β-adrenergic receptor (β-AR) and the transiently transfected human bradykinin (BK) B₂receptor (B₂R). When β-AR and B₂R are costimulated, we found two different cross talk mechanisms. First, the predominantly G_q protein-coupled B₂R is enabled to activate a G_i protein and, subsequently, type II adenylate cyclase. This results in augmentation of β-AR-mediated cyclic AMP (cAMP) accumulation by BK, which alone is unable to increase the cAMP level. Second, independently of BK-induced superactivation of the cAMP system, costimulation of β-AR leads to protein kinase A-mediated blockade of phospholipase C activation by BK. Thereby, the pathway from B₂R to MAPK, which essentially involves protein kinase C activation, is selectively switched off. The MAPK activation in response to isoproterenol was not affected due to costimulation. Furthermore, in the presence of isoproterenol, BK lost its ability to stimulate DNA synthesis in COS-7 cells. Thus, our findings might establish a novel paradigm: cooperation between simultaneously activated mitogenic pathways may prevent multiple stimulation of MAPK activity and increased cell growth.

ACKNOWLEDGMENTS

We thank C. Mertens and B. Haarseim for excellent technical support and H. Traber and H. Sack for help in preparation of the figures. We thank Günter Schultz for generous support.

This work was supported by grants from Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie to C.L. and B.N.