Channel β2-4 subunits fail to substitute for β1 in sensitizing BK channels to lithocholate
Channel β2-4 subunits fail to substitute for β1 in sensitizing BK channels to lithocholate
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DOI：
10.1016/j.bbrc.2009.10.091
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发表时间：
2009-12-18
影响因子：
3.1
通讯作者：
Dopico, Alejandro M.
中科院分区：
文献类型：
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作者：
Bukiya, Anna N.;Vaithianathan, Thirumalini;Dopico, Alejandro M.
大电导、钙门控和电压门控钾 (BK) 通道调节许多生理过程。虽然天然 BK 通道的大多数基本功能特征是由 BK α (slo1) 亚基同四聚体再现的，但关键的生物物理和药理学特性因辅助 β 亚基（由 KCNMB1-4 编码）的存在而发生巨大改变。许多生理类固醇，包括性激素、糖皮质激素和盐皮质激素，都会激活含有 β 亚基的 BK 通道，但这些类固醇似乎可以被不同类型的 β 亚基感知，其中一些类固醇也可以被同源 slo1 通道感知。我们最近表明，β1 使 BK 通道对 mu M 浓度的石胆酸盐 (LC) 敏感。在非洲爪蟾卵母细胞中表达具有β1、β2、β3或β4的大鼠大脑动脉肌细胞slo1亚基（“cbv1”）后，我们现在证明BKβ2、β3和β4亚基无法替代β1来为BK通道提供LC敏感性（150μM）。这些发现首次记录了 BK 通道通过特定通道辅助亚基的相当选择性的类固醇激活。此外，LC 经常激活从大鼠脑动脉平滑肌中新鲜分离的肌细胞中的天然 BK 通道，其中 BK β 1 高表达，而在骨骼肌（趾短屈肌）中则无法激活，其中 BK β 1 表达可以忽略不计。这表明 BK 通道的天然环境维持了 β1 亚基明显向 BK 通道提供的 LC 敏感性。我们的研究表明，LC 是一种独特的工具，可探测功能性 β1 亚基的存在并选择性激活高度表达 KCNMB1 的组织中的 BK 通道。 (C) 2009 Elsevier Inc. 保留所有权利。
Large conductance, calcium- and voltage-gated potassium (BK) channels regulate numerous physiological processes. While most basic functional characteristics of native BK channels are reproduced by BK alpha (slo1) subunit homotetramers, key biophysical and pharmacological properties are drastically modified by the presence of auxiliary beta subunits (encoded by KCNMB1-4). Numerous physiological steroids, including sex hormones, gluco- and mineralocorticoids, activate beta subunit-containing BK channels, yet these steroids appear to be sensed by different types of beta subunits, with some steroids being sensed by homomeric slo1 channels as well. We recently showed that beta 1 sensitizes the BK channel to mu M concentrations of lithocholate (LC). Following expression of rat cerebral artery myocyte slo1 subunits ("cbv1") with beta 1, beta 2, beta 3 or beta 4 in Xenopus laevis oocytes we now demonstrate that BK beta 2, beta 3 and beta 4 subunits fail to substitute for beta 1 in providing LC-sensitivity (150 mu M) to the BK channel. These findings document for the first time a rather selective steroid activation of BK channels via a particular channel accessory subunit. In addition, LC routinely activated native BK channels in myocytes freshly isolated from rat cerebral artery smooth muscle, where BK beta 1 is highly expressed, while failing to do so in skeletal (flexor digitorum brevis) muscle, where BK beta 1 expression is negligible. This indicates that the native environment of the BK channel sustains the LC-sensitivity distinctly provided to the BK channel by beta 1 subunits. Our study indicates that LC represents a unique tool to probe the presence of functional beta 1-subunits and selectively activate BK channels in tissues that highly express KCNMB1. (C) 2009 Elsevier Inc. All rights reserved.