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

Area of Science:

• Molecular neuroscience
• Biophysics
• Ion channel pharmacology

Background:

• Polyunsaturated fatty acids (PUFAs) modulate ion channel activity.
• Recent studies indicate PUFAs potentiate acid-sensing ion channels (ASICs), but the mechanism is unclear.
• Understanding PUFA effects on ASICs is crucial for ion channel modulation research.

Purpose of the Study:

• To elucidate the mechanism by which PUFAs increase maximal current in ASIC3.
• To investigate the interaction of docosahexaenoic acid (DHA) and N-arachidonyl glycine (AG) with hASIC3.
• To provide a mechanistic explanation for PUFA-induced potentiation of ASICs.

Main Methods:

• All-atom molecular dynamics simulations of open-state hASIC3.
• Electrophysiology, including single-channel recordings.
• Simulations in the presence and absence of PUFAs and analogs.

Main Results:

• Membrane phospholipid (POPC) tails obstruct the hASIC3 pore in simulations without PUFAs.
• DHA and AG binding prevented POPC pore access, relieving the obstruction.
• Single-channel recordings confirmed DHA increases hASIC3 current amplitude.

Conclusions:

• PUFAs, like DHA, relieve an endogenous phospholipid-induced pore block in hASIC3.
• This provides a novel mechanistic explanation for PUFA-mediated potentiation of ASIC maximal current.
• Findings reveal a new mode of ion channel modulation by lipids.