Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, USA.
Dalton Cardiovascular Research Center, University of Missouri - Columbia, Columbia, MO, USA.
Nat Commun. 2022 Nov 9;13(1):6784. doi: 10.1038/s41467-022-34359-6.
BK type Ca-activated K channels activate in response to both voltage and Ca. The membrane-spanning voltage sensor domain (VSD) activation and Ca binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca binding to pore opening are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca dependent activation mechanism. BC5 activates the channel in the absence of Ca binding but Ca binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca dependent activation and is an important site for allosteric agonists to modulate BK channel activation.
BK 型 Ca 激活型钾通道对电压和 Ca 均有反应。跨膜电压传感器域（VSD）的激活和胞质尾域（CTD）与 Ca 的结合打开了膜上的孔，但将 VSD 激活和 Ca 结合与孔打开偶联的机制尚不清楚。在这里，我们展示了一种从计算机筛选中鉴定出的化合物 BC5 与 CTD-VSD 界面相互作用，并特异性调节 Ca 依赖性激活机制。BC5 在没有 Ca 结合的情况下激活通道，但 Ca 结合抑制 BC5 的作用。因此，BC5 扰乱了将 Ca 结合与孔打开偶联的途径，从而变构影响两者，这进一步得到原子模拟和突变的支持。结果表明，CTD-VSD 相互作用对 Ca 依赖性激活机制有重要贡献，是变构激动剂调节 BK 通道激活的重要位点。
