Gating and permeation in cation-selective voltage-gated ion channels

Cation-selective voltage-gated ion channels are integral membrane proteins that play a critical role in normal and abnormal physiology by relaying the transmembrane electric field into the cell. Cation channels can be highly selective, e.g. the class of K+-selective voltage-gated (K v) channels, or non-selective, such as Hyperpolarization-activated Cyclic-Nucleotide modulated (HCN) channels that have significant permeability to both K + and Na+. Selective ion permeation and activation gating in Kv- and HCN channels are traditionally treated as separate, independent and parallel processes in the study of ion channel structure and function. In the series of studies presented here, we present evidence that challenges the prevailing view that ion permeation and activation gating are controlled by structures on opposite sides of the permeation pathway. We have observed that the kinetic and steady-state activation gating behavior of both HCN channels and Kv1.4 channels are acutely sensitive to the precise identity of the amino acid residues in and near the selectivity filter. We propose a model of pore-to-gate coupling in which the pore region interacts allosterically with either the voltage sensor or the activation gate itself. In the case of HCN channels, we have found that this coupling is modulated by the extracellular K+ concentration. Our findings provide insight into the mechanism of gating in voltage-gated ion channels and have implications for the design of mutant ion channels with specifically-tailored gating phenotypes for use in genetically induced bio-pacemakers and other forms of gene therapy.