PUFA modulation of ASIC3 involves both specific and lipid solvent-like interactions

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Inflammatory mediators like polyunsaturated fatty acids (PUFAs) are known to modulate acid-sensing ion channel 3 (ASIC3) function.
• The precise molecular mechanisms underlying PUFA interactions with ASIC3 remain largely undefined.

Purpose of the Study:

• To elucidate the molecular basis of how docosahexaenoic acid (DHA), a PUFA, interacts with and modulates ASIC3 channel function.
• To identify the specific binding site and key residues involved in PUFA potentiation of ASIC3.

Main Methods:

• All-atom molecular dynamics (MD) simulations were employed to visualize DHA accumulation around ASIC3.
• Electrophysiology experiments were conducted to assess the functional consequences of DHA binding and specific mutations.

Main Results:

• DHA was observed to accumulate near ASIC3, interacting with a membrane-facing electropositive region on TM1.
• The carboxylate head group of DHA strongly binds to arginine 63 (R63) in the open channel state, slowing desensitization but not affecting pH sensitivity.
• Mutation of R63 abolished DHA's effects on desensitization, while effects of N-acyl amino acids (NAAAs) and lysophosphatidylcholines (LPCs) remained unaltered.

Conclusions:

• This study provides the first detailed characterization of a functional PUFA binding site on ASIC channels.
• The findings offer novel insights into lipid modulation of ion channel activity and suggest potential therapeutic strategies for pain and inflammation targeting ASIC3-lipid interactions.