Lipid-mediated hydrophobic gating in the BK potassium channel

TL;DR

This study reveals that lipids play a crucial role in gating of the BK potassium channel by modulating pore hydration through hydrophobic interactions, providing a new understanding of ion channel regulation.

Contribution

The paper uncovers a lipid-mediated hydrophobic gating mechanism in BK channels, highlighting lipids as active components in gating rather than passive surroundings.

Findings

Lipids occupy the pore in the closed state, stabilizing a vapor bubble that prevents conduction.

Calcium binding displaces lipids, enabling pore hydration and ion conduction.

The gating mechanism explains experimental observations of state-dependent blocker accessibility.

Abstract

The large-conductance, calcium-activated potassium (BK) channel lacks the typical intracellular bundle-crossing gate present in most ion channels of the 6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore accessibility experiments and recently corroborated by a CryoEM structure of the non-conductive state, raises a puzzling question: how can gating occur in absence of steric hindrance? To answer this question, we carried out molecular simulations and accurate free energy calculations to obtain a microscopic picture of the sequence of events that, starting from a Ca$^{2+}$-free state leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an unexpected role for annular lipids, which turn out to be an integral part of the gating machinery. Due to the presence of fenestrations, the "closed" Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl chains. This dynamic occupancy triggers and stabilizes the nucleation of a vapor bubble into the inner pore cavity, thus hindering ion conduction. By contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside the inner cavity, lowering the hydrophobicity of this region and thus allowing for pore hydration and conduction. This lipid-mediated hydrophobic gating rationalizes several seemingly problematic experimental observations, including the state-dependent pore accessibility of blockers.