Department of Anesthesiology
School of Medicine
660 S. Euclid Ave., St. Louis
Website Chanda Lab
”Structural basis of voltage-dependent gating of a human hyperpolarization and cyclic nucleotide activated ion channel”
Most voltage-gated ion channels activate upon membrane depolarization. However, there is a subset of voltage-gated ion channels, called hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, that activates at negative membrane potentials. The reversed gating polarity of HCN channels is attributed to inverted coupling between voltage-sensor activation and pore opening but the structural basis of this coupling remains unclear. Here, we present structures of a human HCN1 channel in three different states: (a) closed pore with voltage sensors in the resting conformation, (b) closed pore with voltage sensors in intermediate conformation, and (c) open pore with fully activated voltage-sensors. In the open structure, two gating charges move downward relative to the charge transfer center compared to the intermediate state, where only a single gating charge has moved. Remarkably, the downward move of the voltage-sensor is accompanied by progressive unwinding of the lower segment of transmembrane helices S4 and S5. These gating transitions disrupt the tight interactions between S4 and S5 segments in the closed state and result in pore opening. Our new structures are the missing link for understanding the structural mechanism of voltage-dependent opening of hyperpolarization activated ion channels.
Host: Walter SANDTNER
Contact for questions: Helmut KUBISTA