Lipid modulation in a model K⁺ channel occurs through alterations at both, the inner and the outer channel gates

This paper reports on a plausible mechanism of modulation by anionic phospholipids of KcsA, a model prokaryotic potassium channel. A first conclusion is that the association of anionic phospholipids with KcsA occurs at discrete regions located near both the extracellular and intracellular channel gates. This same behaviour is consistently observed in both detergent micelles and lipid bilayer-based experimental systems, indicating that the interaction does not depend on bulk bilayer characteristics. In the outer gate (i.e., the selectivity filter) anionic lipid binding to the so called non-annular lipid binding sites, drives the selectivity filter into a non-inactivating, conductive conformation, with a fairly high affinity to bind K⁺. Likewise, at the inner gate, the anionic lipid binding site seems to include cationic amino acid residues at the so called M0 helix. Here, interaction with anionic lipids facilitates the untangle of the C-terminal α-helical bundle at more neutral pH values, thus, facilitating inner gate opening. Both of these phenomena seem to occur independently and should favour the so called Conductive/Open state in the proposed gating cycle of the channel, which in the absence of anionic lipids is just a short-lived, transient state. Consequently, it is expected that the interactions of anionic lipid with KcsA should result in a great increase in ion channel activity. Indeed, this is the case, as reported in functional studies from different laboratories. Such an ability of specific lipids to regulate channel function points out to an interest in future developments of lipid-like drugs to control channelopathies.