Cross talk between beta-adrenergic and bradykinin B(2) receptors results in cooperative regulation of cyclic AMP accumulation and mitogen-activated protein kinase activity.
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) B(2) receptor (B(2)R). When beta-AR and B(2)R are costimulated, we found two different cross talk mechanisms. First, the predominantly G(q) protein-coupled B(2)R is enabled to activate a G(i) 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 B(2)R 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.
Hanke
S
S
Institut für Biochemie und Biophysik, Biologisch-Pharmazeutische Fakultät, Friedrich-Schiller-Universität, Philosophenweg 12, D-07743 Jena, Germany.
Nürnberg
B
B
Groll
D H
DH
Liebmann
C
C
D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology; D019556:COS Cells; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D000345:Affinity Labels; D001386:Azides; D010716:Phosphatidylinositols; D011943:Receptors, Adrenergic, beta; D018002:Receptors, Bradykinin; D014443:Tyrosine; C031907:GTP gamma-4-azidoanilide; D006160:Guanosine Triphosphate; D004247:DNA; D000242:Cyclic AMP; D066246:ErbB Receptors; D007545:Isoproterenol