A Surprising Clarification of the Mechanism of Ion-channel Voltage-Gating

An intense controversy has surrounded the mechanism of voltage-gating in ion channels. We interpreted the two leading models of voltage-gating with respect to the thermodynamic energetics of membrane insertion of the voltage-sensing 'module' from a comprehensive set of potassium channels. KvAP is an archaeal voltage-gated potassium channel whose x-ray structure was the basis for determining the general mechanism of voltage-gating. The free energy of membrane insertion of the KvAP voltage sensor was revealed to be a single outlier. This was due to its unusual sequence that facilitated large gating movements in its native lipid membrane. This degree of free energy was the least typical of the other voltage sensors, including the Shaker potassium channel. We inferred that the two leading models of voltage-gating referred to alternative mechanisms of voltage-gating: each is applicable to an independent set of ion channels. The large motion of the voltage-sensor during gating proposed by the KvAP-paddle model of gating is unlikely to be mirrored by the majority of ion channels whose voltage sensors are not located at the membrane-cytoplasm interface in the channel closed state.