Molecular Insights\ninto Single-Chain Lipid Modulation\nof Acid-Sensing Ion Channel 3

Polyunsaturated fatty acids (PUFAs) and their analogs\nplay a significant\nrole in modulating the activity of diverse ion channels, and recent\nstudies show that these lipids potentiate acid-sensing ion channels\n(ASICs), leading to increased activity. The potentiation of the channel\nstems from multiple gating changes, but the exact mechanism of these\neffects remains uncertain. We posit a mechanistic explanation for\none of these changes in channel function, the increase in the maximal\ncurrent, by applying a combination of electrophysiology and all-atom\nmolecular dynamics simulations on open-state hASIC3. Microsecond-scale\nsimulations were performed on open-state hASIC3 in the absence and\npresence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analogue, <i>N</i>-arachidonyl glycine (AG). Intriguingly, our simulations\nin the absence of PUFA or PUFA analogs reveal that a tail from the\nmembrane phospholipid POPC inserts itself into the pore of the channel\nthrough lateral fenestrations on the sides of the transmembrane segments,\nobstructing ion permeation through the channel. The binding of either\nDHA or AG prevented POPC from accessing the pore in our simulations,\nwhich relied on the block of ionic conduction by phospholipids. Finally,\nwe use single-channel recording to show that DHA increases the amplitude\nof the single-channel currents in ASIC3, which is consistent with\nour hypothesis that PUFAs relieve the pore block of the channel induced\nby POPCs. Together, these findings offer a potential mechanistic explanation\nof how PUFAs modulate the ASIC maximal current, revealing a novel\nmechanism of action for PUFA-induced modulation of ion channels.