RT info:eu-repo/semantics/article
T1 Tungstate-Targeting of BKαβ1 Channels Tunes ERK Phosphorylation and Cell Proliferation in Human Vascular Smooth Muscle
A1 López López, José Ramón
A1 Fernández Mariño, Ana Isabel
A1 Cidad Velasco, María del Pilar
A1 Zafra, Delia
A1 Nocito, Laura
A1 Domínguez, Jorge
A1 Oliván Viguera, Aida
A1 Köhler, Ralf
A1 Pérez García, María Teresa
A1 Valverde, Miguel Ángel
A1 Guinovart, Joan J.
A1 Fernández Fernández, José Manuel
K1 Calcio
K1 Metabolismo
AB Despite 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 BKαβ1 potassium channel, which modulates vascular 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 protein-dependent manner. Tungstate activated BKαβ1 channels upstream of G proteins as channel activation was not altered by the inhibition of G proteins with GDPβS or pertussis toxin. Moreover, analysis of Gi/o protein activation measuring the FRET among heterologously expressed Gi protein subunits suggested that tungstate-targeting of BKαβ1 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 BKαβ1 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.
PB Plos
SN 1932-6203
YR 2015
FD 2015
LK http://uvadoc.uva.es/handle/10324/29191
UL http://uvadoc.uva.es/handle/10324/29191
LA eng
NO Plos One, 2015, p. 1-21
NO Producción Científica
DS UVaDOC
RD 18-nov-2024