Channel Gating Theory Revised

Abstract

Voltage-gated ion channels, which are opened (or gated) in response to changes in the voltage across the cell membrane, control fundamental signaling properties in cells, particularly in neurons and muscle cells. A great deal of effort has been expended in trying to understand the molecular basis for this behavior. A sensor region of voltage-gated K + channels has been defined and is known to move across the membrane to promote channel gating. Two papers from Jiang and colleagues in the MacKinnon laboratory provide new clues by revealing the structure of the voltage sensor and characterizing its movement in the membrane. X-ray crystal structures of membrane proteins like channels have been very difficult to obtain. Jiang et al. figured that part of the problem might be that the voltage sensor flapped around too much and prevented crystallization of the protein. Indeed, they found that if they pinned down the sensor domains by binding them to an antibody Fab fragment, they could obtain crystals of KvAP, a bacterial channel that is similar to mammalian voltage-gated K + channels. Structural analysis revealed that the voltage sensor appears to be a hydrophobic helix-turn-helix structure that the authors call a voltage-sensor paddle. If one assumes that the crystals accurately represent the conformation of the functional receptor in a membrane, the paddle appears to sit near the intracellular surface of the membrane. Although previous models suggested that the sensor might move within the proteinaceous channel complex of four subunits, the new structure indicates that the paddle instead likely moves through the membrane itself on the channel perimeter. This may explain pharmacological data showing that small lipid-soluble molecules easily access the voltage sensor. On the basis of the structure, the authors tagged key positions in the voltage sensor with biotinylated cysteine residues and monitored the presence of the sensor on the inner or outer surface of the membrane by measuring avidin binding. These experiments confirmed that the paddles flop back and forth through the membrane in response to voltage changes, acting as what the authors call hydrophobic cations attached to levers. Sigworth provides commentary on these results. Y. Jiang, A. Lee, J. Chen, V. Ruta, M. Cadene, B. T. Chait, R. Mackinnon, X-ray structure of a voltage-dependent K + channel. Nature 432 , 33-41 (2003). [Online Journal] Y. Jiang, V. Ruta, J. Chen, A. Lee, R. Mackinnon, The principle of gating charge movement in a voltage-dependent K + channel. Nature 432 , 42-48 (2003). [Online Journal] F. J. Sigworth, Life's transistors. Nature 432 , 21-22 (2003). [Online Journal]