Electrophysiological characterization of benzofuroindole-induced potentiation of large-conductance Ca2+-activated K+ channels.

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.