A hydrophobic funnel governs monovalent cation selectivity in the ion channel TRPM5

Abstract

A key capability of ion channels is the facilitation of selective permeation of certain ionic species across cellular membranes at high rates. Due to their physiological significance, ion channels are of great pharmaceutical interest as drug targets. The polymodal signal-detecting Transient Receptor Potential (TRP) superfamily of ion channels form a particularly promising group of drug targets. While most members of this family permeate a broad range of cations, TRPM4 and TRPM5 are unique due to their strong monovalent-selectivity and impermeability for divalent cations. Here, we address the mechanistic basis for their unique monovalent-selectivity. We present results from in silico electrophysiology simulations of cation permeation through the TRPM5 channel, showing that monovalent cations permeate by a co-operative, distant knock-on mechanism between cation binding sites in the extracellular pore vestibule and the pore cavity. By contrast, divalent cations experience an energy barrier within the pore cavity, which inhibits their permeation via a knock-on mechanism.