Zakharov Sergey I, Morrow John P, Liu Guoxia, Yang Lin, Marx Steven O
Division of Cardiology, Department of Medicine and Pharmacology and Center for Molecular Cardiology and Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Biol Chem. 2005 Sep 2;280(35):30882-7. doi: 10.1074/jbc.M505302200. Epub 2005 Jul 5.
Pharmacologic approaches to activate K+ channels represent an emerging strategy to regulate membrane excitability. Here we report the identification and characterization of a lipid soluble toxin, mallotoxin (rottlerin), which potently activates the large conductance voltage and Ca2+-activated K+ channel (BK) expressed in a heterologous expression system and human vascular smooth muscle cells, shifting the conductance/voltage relationship by >100 mV. Probing the mechanism of action, we discover that the BK channel can be activated in the absence of divalent cations (Ca2+, Mg2+), suggesting that the mallotoxin mechanism of action involves the voltage-dependent gating of the channel. Mallotoxin-activated channels remain incrementally sensitive to Ca2+ and beta subunits. In comparison to other small hydrophobic poisons, anesthetic agents, and protein toxins that inhibit ion channel activity, mallotoxin potently activates channel activity. In certain respects, mallotoxin acts as a BK channel beta1 subunit mimetic, preserving BK channel Ca2+ sensitivity yet adjusting the set-point for BK channel activation to a more hyperpolarized membrane potential.
激活钾离子通道的药理学方法是调节膜兴奋性的一种新兴策略。在此，我们报告了一种脂溶性毒素——毛喉素（rottlerin）的鉴定和特性，它能有效激活在异源表达系统和人血管平滑肌细胞中表达的大电导电压和钙离子激活的钾离子通道（BK），使电导/电压关系向超极化方向移动超过100 mV。通过探究其作用机制，我们发现BK通道在没有二价阳离子（Ca2+、Mg2+）的情况下也能被激活，这表明毛喉素的作用机制涉及通道的电压依赖性门控。毛喉素激活的通道对Ca2+和β亚基仍保持递增敏感性。与其他抑制离子通道活性的小疏水毒物、麻醉剂和蛋白质毒素相比，毛喉素能有效激活通道活性。在某些方面，毛喉素起到了BK通道β1亚基模拟物的作用，保留了BK通道对Ca2+的敏感性，但将BK通道激活的设定点调整到了更超极化的膜电位。
