Molecular Insights into Single-Chain Lipid Modulation of Acid-Sensing Ion Channel 3

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• Polyunsaturated fatty acids (PUFAs) modulate ion channel activity.
• Recent studies indicate PUFAs potentiate acid-sensing ion channels (ASICs), increasing their activity.
• The precise mechanism behind PUFA-induced ASIC potentiation remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which PUFAs increase the maximal current of hASIC3.
• To investigate the role of phospholipid interactions within the ASIC pore.

Main Methods:

• All-atom molecular dynamics simulations of open-state hASIC3 with and without docosahexaenoic acid (DHA) and N-arachidonyl glycine (AG).
• Electrophysiology, including single-channel recording, to validate simulation findings.
• Analysis of ion permeation pathways and lipid interactions within the channel pore.

Main Results:

• In simulations without PUFAs, phospholipid (POPC) tails accessed the hASIC3 pore via lateral fenestrations, obstructing ion flow.
• Both DHA and AG binding prevented POPC from entering the pore, thereby relieving the block.
• Single-channel recordings confirmed that DHA increases the amplitude of hASIC3 currents, supporting the pore block relief hypothesis.

Conclusions:

• PUFAs, like DHA, can prevent endogenous phospholipids from blocking the hASIC3 pore.
• This phospholipid-induced pore block and its relief by PUFAs offer a mechanistic explanation for increased ASIC maximal current.
• These findings reveal a novel mechanism for PUFA modulation of ion channel function.