voltage-dependent gating in a “voltage sensor-less” ion channel压敏电阻器控制电压传感器不u201c离子通道.pdfVIP

Voltage-Dependent Gating in a ‘‘Voltage Sensor-Less’’ Ion Channel 1 2 3,4 2 3,4 Harley T. Kurata *, Markus Rapedius , Marc J. Kleinman , Thomas Baukrowitz , Colin G. Nichols * 1 Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, Canada, 2 Institute of Physiology II, Friedrich Schiller University, Jena, Germany, 3 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 4 Center for Investigation of Membrane Excitability Disorders (CIMED), Washington University School of Medicine, St. Louis, Missouri, United States of America Abstract The voltage sensitivity of voltage-gated cation channels is primarily attributed to conformational changes of a four transmembrane segment voltage-sensing domain, conserved across many levels of biological complexity. We have identified a remarkable point mutation that confers significant voltage dependence to Kir6.2, a ligand-gated channel that lacks any canonical voltage-sensing domain. Similar to voltage-dependent Kv channels, the Kir6.2[L157E] mutant exhibits time-dependent activation upon membrane depolarization, resulting in an outwardly rectifying current-voltage relationship. This voltage dependence is convergent with the intrinsic ligand-dependent gating mechanisms of Kir6.2, since increasing the membrane PIP2 content saturates Po and eliminates voltage dependence, whereas voltage activation is more dramatic when channel Po is reduced by application of ATP or poly-lysine. The