Role of cytoplasmic cap in determining the ion selectivity of P2X receptor channels

Abstract

Trimeric P2X receptors are ATP-activated ion channels, with each subunit consisting of an intracellular N- and C- termini, a large extracellular domain forming ATP binding sites, and two transmembrane helices (TMs) that form an ion permeation pathway. In recent structures of human P2X3 receptors, a cytoplasmic cap formed by the N- and C- termini covers the central ion permeation pathway, leaving only small lateral fenestrations near or within the membrane for ions to enter or exit the pore. To investigate whether these fenestrations play a role in determining the ion selectivity of P2X receptors, we identified an acidic residue (E17 in rP2X2) that lines the lateral fenestrations and is conserved in subtypes that are cation selective but replaced by a basic residue in P2X5 receptors (K17 in mP2X5), a subtype reported to have significant chloride permeability.