title: Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation.
abstract: The beta3 adrenergic receptor (B3-AR) reportedly induces cell proliferation, but the signaling pathways that were proposed, involving either Gs or Gi coupling, remain controversial. To further investigate the role of G protein coupling in B3-AR induced proliferation, we stimulated primary human myometrial smooth muscle cells with SAR150640 (B3-AR agonist) in the absence or presence of variable G-protein inhibitors. Specific B3-AR stimulation led to an Erk1/2 induced proliferation. We observed that the proliferative effects of B3-AR require two Erk1/2 activation peaks (the first after 3min, the second at 8h). Erk1/2 activation at 3min was mimicked by forskolin (adenylyl-cyclase activator), and was resistant to pertussis toxin (Gi inhibitor), suggesting a Gs protein signaling. This first signaling also required the downstream Gs signaling effectors PKA and Src. However, Erk1/2 activation at 8h turned out to be pertussis toxin-dependent, and PKA-independent, indicating a Gi signaling pathway in which Src and PI3K were required. The pharmacological inhibition of both the Gs and Gi pathway abolished B3-AR-induced proliferation. Altogether, these data indicate that B3-AR-induced proliferation depends on the biphasic activation of Erk1/2 sequentially induced by the Gs/PKA/Src and Gi/Src/PI3K signaling pathways.
authors: Lipides Nutrition Cancer, Dijon, France.
authors: Tarik
authors: T
authors: Hadi
authors: Marina
authors: M
authors: Barrichon
authors: Pascal
authors: P
authors: Mourtialon
authors: Maeva
authors: M
authors: Wendremaire
authors: Carmen
authors: C
authors: Garrido
authors: Paul
authors: P
authors: Sagot
authors: Marc
authors: M
authors: Bardou
authors: Frédéric
authors: F
authors: Lirussi
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009215:Myometrium / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs