Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation

6533b82ffe1ef96bd12946eb

RESEARCH PRODUCT

Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation

Marc Bardou Marina Barrichon Marina Barrichon Maeva Wendremaire Maeva Wendremaire Paul Sagot Carmen Garrido Carmen Garrido Frédéric Lirussi Tarik Hadi Tarik Hadi Pascal Mourtialon

subject

Beta-3 adrenergic receptor Gs alpha subunit MAP Kinase Signaling System Myocytes Smooth Muscle Proliferation G protein coupled receptor Biology GTP-Binding Protein alpha Subunits Gi-Go Pertussis toxin chemistry.chemical_compound Erk1/2 Protein kinases Cyclins Receptors Adrenergic beta GTP-Binding Protein alpha Subunits Gs Humans Molecular Biology PI3K/AKT/mTOR pathway Cells Cultured G protein-coupled receptor Cell Proliferation Forskolin Colforsin Beta-3 adrenergic receptor Cell Biology Cell biology chemistry Gene Expression Regulation Pertussis Toxin Myometrium Female Signal transduction Proto-oncogene tyrosine-protein kinase Src

description

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 3 min, the second at 8 h). Erk1/2 activation at 3 min 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 8 h 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.

year	journal	country	edition	language
2013-05-01	Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

10.1016/j.bbamcr.2013.01.019 http://dx.doi.org/10.1016/j.bbamcr.2013.01.019