title: DiBAC₄(3) hits a "sweet spot" for the activation of arterial large-conductance Ca²⁺-activated potassium channels independently of the β₁-subunit.
abstract: The voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC₄(3)] has been reported as a novel large-conductance Ca²⁺-activated K⁺ (BK) channel activator with selectivity for its β₁- or β₄-subunits. In arterial smooth muscle, BK channels are formed by a pore-forming α-subunit and a smooth muscle-abundant regulatory β₁-subunit. This tissue specificity has driven extensive pharmacological research aimed at regulating arterial tone. Using animals with a disruption of the gene for the β₁-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 α-subunit. We studied BK channels from wild-type and transgenic β₁-knockout mice in excised patches. BK channels from brain arteries, with or without the β₁-subunit, were similarly activated by DiBAC₄(3). In addition, we found that saturating concentrations of DiBAC₄(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 Ca²⁺ and/or the β₁₋₄-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.
authors.affiliation: Cardiovascular Genetics Center, Institut de Investigació Biomèdica de Girona, and Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Scornik
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Bucciero
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Elisabet
authors.initials: E
authors.lastname: Selga
authors.forename: Cristina
authors.initials: C
authors.lastname: Bosch Calero
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Pérez
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001463:Barbiturates / Q000378:metabolism / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004285:Dogs; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000187:drug effects* / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000235:genetics; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D001463:Barbiturates; D007555:Isoxazoles; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015222:Sodium Channels; C052795:bis(1,3-dibutylbarbiturate)trimethine oxonol
keywords: BK channels; DiBAC4(3), KCNMA1; KCNMB1; arterial smooth muscle
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