Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

• DOI: 10.1038/s42003-021-01678-1
• Publication Date: 2021-02-09T21:23:32Z
• Authors: Yi Liu; Jichun Ma; Renee L. DesJarlais; Rebecca Hagan; Jason Rech; David Lin; Changlu Liu; Robyn Miller; Jeffrey Schoellerman; Jinquan Luo; Michael Letavic; Bruce Grasberger; Michael Maher
• Keywords: Acid-sensing ion channel; Modulation (music)

Abstract Acid-sensing ion channels (ASICs) are proton-gated cation critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in residues, as key participant channel gating. While binding to this by the venom peptide psalmotoxin modulates gating, molecular structural mechanisms gating modulation small molecules poorly understood. Here, combining functional, crystallographic, computational mutational approaches, we show that two structurally distinct potently allosterically inhibit activation desensitization at pocket stabilizing closed state rat/chicken ASIC1. Our work identifies previously unidentified site, elucidates mechanism molecule demonstrates directly basis such modulation, providing mechanistic insight into therapeutic targeting.