Activation and peptide modulation of an acid-sensing ion channel involves conformationally decoupled states

Abstract

Acid-sensing ion channels (ASICs) contribute to fast synaptic transmission and are controlled by protonation of residues in the extracellular domain (ECD) that lead to opening of the cation-selective pore in the transmembrane domain (TMD) of this trimeric channel. By binding to the subunit interface of the ASIC1a ECD, the cysteine knot toxin Psalmotoxin-1 (PcTx1) can potently and selectively inhibit the channel leading to reduce neurotoxicity during ischemic strokes. However, the conformational consequences of this interaction and the number of toxin molecules required for inhibition have remained unknown.