A commentary on the article is available here.

Among neurotransmitter-gated ion channels, the superfamily of pentameric ligand-gated ion channels (pLGICs) is unique in that its members display opposite permeant-ion charge selectivities despite sharing the same structural fold. Although much effort has been devoted to the identification of the mechanism underlying the cation-versus-anion selectivity of these channels, a careful analysis of past work reveals that discrepancies exist, that different explanations for the same phenomenon have often been put forth, and that no consensus view has yet been reached. Here, the authors present compelling evidence for the critical involvement of ionized side chains—whether pore-facing or buried—rather than backbone atoms and propose a mechanism whereby not only their charge sign, but also, their conformation determines charge selectivity.