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 ␤-adrenergic receptor (␤-AR) and the transiently transfected human bradykinin (BK) B 2 receptor (B 2 R). When ␤-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 ␤-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 ␤-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.

Induction of Adherent Activity in Mastocytoma P-815 Cells by the Cooperation of Two Prostaglandin E2 Receptor Subtypes, EP3 and EP4

“…Very recently, activation of a G i -coupled receptor has been reported to augment the adenylyl cyclase activity induced by the stimulation of a G s -coupled receptor in COS-7 cells. For example, activation of G i -coupled receptors such as ␣2 adrenoreceptor (29) and bradykinin B2 receptor (32) lead to the augmentation of G s -stimulated adenylyl cyclase in COS-7 cells. This synergistic effect has not been clearly shown in mammalian cells.…”

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

“…As a result of the poor transfection efficiency of BAEC, we further investigated the mechanisms involved in the MT1-MMP -dependent transactivation of EGFR using COS-7 cells. This cell type has been used in number of studies to determine the signaling mechanisms involved in GPCR-mediated transactivation of EGFR (32,(40)(41)(42)(43)(44). These cells contain detectable amounts of the S1P receptor S1P 1 (45), but no detectable MT1-MMP, and thus constitute an interesting and appropriate cell model to study the mechanisms involved in S1P-stimulated MT1-MMP -dependent EGFR transactivation.…”

Bradykinin B2and GPR100 receptors: a paradigm for receptor signal transduction pharmacology

“…A difference in Icatibant potency towards contractile effects elicited by BK and FR190997 had been previously observed in the guinea-pig ileum smooth muscle (Meini et al, 2000). Since the possibility of a regulation between adenylyl cyclase and phospholipase C activity has been reported (Campbell et al, 1990;Boyajian et al, 1991;Hanke et al, 2001), it remains to be established whether this inhibitory activity of FR190997, which is not blocked by Icatibant, is responsible for the tissue/cell-dependent agonist/antagonist profile of FR190997 (Rizzi et al, 1999). To our knowledge, this is the first evidence showing that the synthetic ligand FR190997 can activate an inhibitory adenylyl cyclase pathway, which although not antagonized by Icatibant can be considered B 2 receptor dependent, since it is not observable in cells expressing GPR100 or in not transfected CHO cells.…”

“…Moreover, BK is able to produce a mitogenic effect by stimulating the mitogenactivated protein kinase via Gai coupling. This Gai-coupled (pertussis toxin sensitive) B 2 receptor activity has been shown to be specific for certain tumor cell lines, such as the human breast carcinoma EFM-192A and the small-cell lung carcinoma H-69 (Drube & Liebmann, 2000), or the human endometrium carcinoma cell line EFE-184 (Liebmann, 2001), and also in COS-7 cells transfected with the hB 2 R (Hanke et al, 2001). It is worth mentioning that Icatibant behaved as BK in activating the mitogenic signal in cell systems both coupled to Gai or Gaq protein (Drube & Liebmann, 2000), although in the presented cell system it did not produce any agonist effect.…”