DiBAC(4)(3) hits a %26quot;sweet spot%26quot; for the activation of arterial large-conductance Ca2+-activated potassium channels independently of the beta(1)-subunit

作者：Scornik Fabiana S; Bucciero Ronald S; Wu Yuesheng; Selga Elisabet; Bosch Calero Cristina; Brugada Ramon; Perez Guillermo J^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2013, 304(11): H1471-H1482.

DOI：10.1152/ajpheart.00939.2012

• BK channels
• arterial smooth muscle
• DiBAC(4)(3)
• KCNMA1
• KCNMB1

The voltage-sensitive dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC(4)(3)] has been reported as a novel large-conductance Ca2+ activated K+ (BK) channel activator with selectivity for its beta(1)- or beta(4)-subunits. In arterial smooth muscle, BK channels are formed by a pore-forming alpha-subunit and a smooth muscle-abundant regulatory beta(1)-subunit. This tissue specificity has driven extensive pharmacological research aimed at regulating arterial tone. Using animals with a disruption of the gene for the beta(1)-subunit, we explored the effects of DiBAC(4)(3) in native channels from arterial smooth muscle. We tested the hypothesis that, in native BK channels, activation by DiBAC(4)(3) relies mostly on its alpha-subunit. We studied BK channels from wildtype and transgenic beta(1)-knockout mice in excised patches. BK channels from brain arteries, with or without the beta(1)-subunit, were similarly activated by DiBAC4(3). In addition, we found that saturating concentrations of DiBAC4(3) (similar to 30 mu M) promote an unprecedented persistent activation of the channel that negatively shifts its voltage dependence by as much as -300 mV. This %26quot;sweet spot%26quot; for persistent activation is independent of Ca2+ and/or the -1-4-subunits and is fully achieved when DiBAC(4)(3) is applied to the intracellular side of the channel. Arterial BK channel response to DiBAC(4)(3) varies across species and/or vascular beds. DiBAC(4)(3) unique effects can reveal details of BK channel gating mechanisms and help in the rational design of BK channel activators.

• 出版日期2013-6