In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 304, No. 11 ( 2013-06-01), p. H1471-H1482
Abstract:
The voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC 4 (3)] has been reported as a novel large-conductance Ca 2+ -activated K + (BK) channel activator with selectivity for its β 1 - or β 4 -subunits. In arterial smooth muscle, BK channels are formed by a pore-forming α-subunit and a smooth muscle-abundant regulatory β 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 β 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 α-subunit. We studied BK channels from wild-type and transgenic β 1 -knockout mice in excised patches. BK channels from brain arteries, with or without the β 1 -subunit, were similarly activated by DiBAC 4 (3). In addition, we found that saturating concentrations of DiBAC 4 (3) (∼30 μM) 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 2+ and/or the β 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.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00939.2012
Language:
English
Publisher:
American Physiological Society
Publication Date:
2013
detail.hit.zdb_id:
1477308-9
SSG:
12
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