Ha Tal Soo, Lim Hyun-Ho, Lee Ga Eun, Kim Yong-Chul, Park Chul-Seung
Department of Life Science, Gwangju Institute of Science and Technology, Bukgu, Gwangju, 500-712, Korea.
Mol Pharmacol. 2006 Mar;69(3):1007-14. doi: 10.1124/mol.105.016170. Epub 2005 Dec 6.
Large-conductance Ca2+-activated K+ (BK(Ca)) channels are widely distributed and play key roles in various cell functions. We previously reported the chemical synthesis of several benzofuroindole compounds that act as potent openers of BK(Ca) channels. In this study, we investigated the mechanism of channel potentiation by one of the compounds, 7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), using electrophysiological means. This chemical highly activated cloned BK(Ca) channels from extracellular side independent of beta subunits and regardless of the presence of intracellular Ca2+. The EC50 and Hill coefficient for rat BK(Ca) channel alpha subunit, rSlo, were estimated as 8.9 +/- 1.5 microM and 0.9, respectively. TBIC shifted the conductance-voltage curve of rSlo channels to more hyperpolarized potentials without altering its voltage dependence. Single-channel recording revealed that TBIC increased the open probability of the channel in a dose-dependent manner without any changes in single-channel conductance. Strong potentiation by TBIC was also observed for native BK(Ca) channels from rat hippocampus pyramidal neurons. Thus, TBIC and the related benzofuroindole compounds can be useful tools to unravel the mechanism of this novel allosteric activation of BK(Ca) channels.
大电导钙激活钾（BK(Ca)）通道广泛分布，在各种细胞功能中发挥关键作用。我们之前报道了几种苯并呋喃吲哚化合物的化学合成，这些化合物可作为BK(Ca)通道的有效开放剂。在本研究中，我们使用电生理方法研究了其中一种化合物7-三氟甲基-10H-苯并[4,5]呋喃[3,2-b]吲哚-1-羧酸（TBIC）增强通道活性的机制。这种化合物可从细胞外侧高度激活克隆的BK(Ca)通道，与β亚基无关，且不受细胞内Ca2+存在与否的影响。大鼠BK(Ca)通道α亚基rSlo的半数有效浓度（EC50）和希尔系数分别估计为8.9±1.5微摩尔和0.9。TBIC将rSlo通道的电导-电压曲线向更超极化的电位移动，而不改变其电压依赖性。单通道记录显示，TBIC以剂量依赖的方式增加通道的开放概率，而单通道电导没有任何变化。在大鼠海马锥体神经元的天然BK(Ca)通道中也观察到TBIC的强烈增强作用。因此，TBIC和相关的苯并呋喃吲哚化合物可能是揭示BK(Ca)通道这种新型变构激活机制的有用工具。
