Identification of PUFA interaction site on ASIC3 suggests a complex regulatory mechanism

DHA binds a membrane-facing electropositive region along TM1 of ASIC3, and an open-state buried site exposes an arginine-dependent interaction that is required for DHA-linked gating effects.

• Why it matters: Inflammatory PUFAs potentiate ASIC3, but the molecular interaction site and how it shapes channel gating and proton sensitivity were unclear.
• What they did: Using all-atom MD simulations plus electrophysiology, the study mapped DHA accumulation around TM1 and tested site-directed mutations that disrupt the carboxylate–arginine and nearby polar-residue contacts.
• The result: Mutations at this DHA site eliminate DHA-mediated slowing of channel desensitization and modestly reduce PUFA effects on proton sensitivity, while leaving regulation by other lipid classes like N-acyl amino acids and lysophosphatidyl choline intact.

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