DiBAC4(3) hits a “sweet spot” for the activation of arterial large-conductance Ca -activated potassium channels independently of the 1-subunit

Scornik FS, Bucciero RS, Wu Y, Selga E, Bosch Calero C, Brugada R, Pérez GJ. DiBAC4(3) hits a “sweet spot” for the activation of arterial large-conductance Ca -activated potassium channels independently of the 1-subunit. Am J Physiol Heart Circ Physiol 304: H1471–H1482, 2013. First published March 29, 2013; doi:10.1152/ajpheart.00939.2012.—The voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)] has been reported as a novel large-conductance Ca activated K (BK) channel activator with selectivity for its 1or 4-subunits. In arterial smooth muscle, BK channels are formed by a pore-forming -subunit and a smooth muscle-abundant regulatory 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 1-subunit, we explored the effects of DiBAC4(3) in native channels from arterial smooth muscle. We tested the hypothesis that, in native BK channels, activation by DiBAC4(3) relies mostly on its -subunit. We studied BK channels from wildtype and transgenic 1-knockout mice in excised patches. BK channels from brain arteries, with or without the 1-subunit, were similarly activated by DiBAC4(3). In addition, we found that saturating concentrations of DiBAC4(3) ( 30 M) promote an unprecedented persistent activation of the channel that negatively shifts its voltage dependence by as much as 300 mV. This “sweet spot” for persistent activation is independent of Ca and/or the 1–4-subunits and is fully achieved when DiBAC4(3) is applied to the intracellular side of the channel. Arterial BK channel response to DiBAC4(3) varies across species and/or vascular beds. DiBAC4(3) unique effects can reveal details of BK channel gating mechanisms and help in the rational design of BK channel activators.