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Molecular and Cellular Biology, December 2001, p. 8452-8460, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8452-8460.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cross Talk between beta -Adrenergic and Bradykinin B2 Receptors Results in Cooperative Regulation of Cyclic AMP Accumulation and Mitogen-Activated Protein Kinase Activity

Sabine Hanke,1 Bernd Nürnberg,2,3 Detlef H. Groll,3 and Claus Liebmann1,*

Institut für Biochemie und Biophysik, Biologisch-Pharmazeutische Fakultät, Friedrich-Schiller-Universität, D-07743 Jena,1 Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, D-14195 Berlin-Dahlem,2 and Abteilung für Pharmakologie und Toxikologie, Universität Ulm, D-89069 Ulm,3 Germany

Received 6 October 2000/Returned for modification 15 December 2000/Accepted 21 September 2001

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 beta -adrenergic receptor (beta -AR) and the transiently transfected human bradykinin (BK) B2 receptor (B2R). When beta -AR and B2R are costimulated, we found two different cross talk mechanisms. First, the predominantly Gq protein-coupled B2R is enabled to activate a Gi protein and, subsequently, type II adenylate cyclase. This results in augmentation of beta -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 beta -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.

* Corresponding author. Mailing address: Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-Universitität Jena, Philosophenweg 12, D-07743 Jena, Germany. Phone: 49-3641-949357. Fax: 49-3641-949352. E-mail: b9licl{at}rz.uni-jena.de.

Molecular and Cellular Biology, December 2001, p. 8452-8460, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8452-8460.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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