Intrinsic Opening of BK Channels Derives from Inherent Leakage in Hydrophobic Gating.

The big potassium (BK) channels remain open with a small limiting probability of ~ 10 at minimal Ca and negative voltages < -100 mV. The molecular origin and functional significance of such "intrinsic opening" are not understood. Here we combine atomistic simulations and electrophysiological experiments to show that the intrinsic opening of BK channels is an inherent property of the vapor barrier, generated by hydrophobic dewetting of the BK inner pore in the deactivated state. The vapor barrier only gives rise to a finite free energy barrier, of ~ 8 kcal/mol, and cannot completely shut down K flow even when the voltage sensor domains are fully deactivated. This results in the leaking currents that can be measured at negative voltages as the indication of intrinsic opening. The shallow limiting slope of at negative voltages results primarily from the electric field effects on the permeating ion through the vapor barrier. We further demonstrate that the vapor barrier can be perturbed by inner pore mutations and truncation of the cytosolic domains, leading to predicable changes in limiting slope measurements. Therefore, the intrinsic opening in BK channels, and possibly in other ion channels, opens up an opportunity to experimentally study hydrophobic gating. Our results further suggest that intrinsic opening in BK channels is the fundamental basis for the allosteric mechanism of activation by both voltage and Ca.