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Tungstate-targeting of BKαβ1 channels tunes ERK phosphorylation and cell proliferation in human vascular smooth muscle

AutorFernández-Mariño, Ana Isabel; Cidad, Pilar ; López-López, José R. ; Pérez-García, M. Teresa ; Fernández-Fernández, José M.
Fecha de publicación2015
EditorPublic Library of Science
CitaciónPLoS ONE 10(2): 30118148 (2015)
ResumenDespite the substantial knowledge on the antidiabetic, antiobesity and antihypertensive actions of tungstate, information on its primary target/s is scarce. Tungstate activates both the ERK1/2 pathway and the vascular voltage- and Ca2+-dependent large-conductance BKαβ smooth muscle cell (VSMC) proliferation and function, respectively. Here, we have assessed the possible involvement of BKαβ1 channels in the tungstate-induced ERK phosphorylation and its relevance for VSMC proliferation. Western blot analysis in HEK cell lines showed that expression of vascular BKαβ1 channels potentiates the tungstate-induced ERK1/2 phosphorylation in a Gi/o proteindependent manner. Tungstate activated BKαβ1 channels upstream of G proteins as channel activation was not altered by the inhibition of G proteins with GDPβ S or pertussis toxin. Moreover, analysis of Gi/o protein activation measuring the FRET among heterologously expressed G i protein subunits suggested that tungstate-targeting of BK αβ1 channels promotes G protein activation. Single channel recordings on VSMCs from wild-type and β1-knockout mice indicated that the presence of the regulatory β1 subunit was essential for the tungstate-mediated activation of BK channels in VSMCs. Moreover, the specific BK channel blocker iberiotoxin lowered tungstate-induced ERK phosphorylation by 55% and partially reverted (by 51%) the tungstate-produced reduction of platelet-derived growth factor (PDGF)-induced proliferation in human VSMCs. Our observations indicate that tungstate-targeting of BK αβ1 channels promotes activation of PTX-sensitive Gi proteins to enhance the tungstate-induced phosphorylation of ERK, and inhibits PDGF-stimulated cell proliferation in human vascular smooth muscle.
DescripciónThis is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al.
Versión del editorhttp://dx.doi.org/10.1371/journal.pone.0118148
Identificadoresdoi: 10.1371/journal.pone.0118148
issn: 1932-6203
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