Voltage sensing in ion channels: a 50-year-old mystery resolved?

CONTEXT: Membrane-protein ion channels control electrical activity in the nervous system. Voltage-gated channels have four-fold symmetry, with a central pore domain surrounded by voltage-sensor regions. Each voltage-sensor region has a positively charged transmembrane helix, S4, which carries gating charges through the membrane on opening or closing. How S4 moves at gating is debated: either S4 moves in a helical screw or in a helical twist pattern. In both cases S4 is assumed to move inside the densely packed channel protein. The pore region was visualised when Roderick MacKinnon's group crystallised a bacterial K+ channel in 1998. The voltage-sensor region and the S4 movement are more difficult to visualise, because voltage-gated channels are harder to crystallise. STARTING POINT: Recently, Yuoxing Jiang and colleagues in MacKinnon's group reported the first successful crystallisation and X-ray analysis of a voltage-gated channel (Nature 2003; 423: 33-41, 42-48), with unexpected results. S4 forms a hairpin loop with another helix, stretching out from the channel perimeter rather than being located inside the densely-packed protein core. This finding suggests a novel type of S4 movement at gating, a paddle sweeping through the lipid bilayer in response to voltage changes. WHERE NEXT? Jiang and colleagues' unexpected results are controversial. Several predictions of the model are incompatible with other experimental data. However, if the paddle configuration is real, it opens up a new field for pharmacological rethinking. Such a configuration may help to understand certain aspects of the action of lipid-soluble gating modifiers, such as local and general anaesthetics and antiarrythmic and antiepileptic agents.