Voltage-gated ion channels sense transmembrane voltage changes via a paddle-shaped motif that includes the C-terminal part of the third transmembrane segment (S3b) and the N-terminal part of the fourth segment ((NT)S4) that harbors voltage-sensing arginines. Here, we find that residue triplets in S3b and (NT)S4 can be deleted individually, or even in some combinations, without compromising the channels' basic voltage-gating capability. Thus, a high degree of complementarity between these S3b and (NT)S4 regions is not required for basic voltage gating per se. Remarkably, the voltage-gated Shaker K(+) channel remains voltage gated after a 43 residue paddle sequence is replaced by a glycine triplet. Therefore, the paddle motif comprises a minimal core that suffices to confer voltage gating in the physiological voltage range, and a larger, modulatory part. Our study also shows that the hydrophobic residues between the voltage-sensing arginines help set the sensor's characteristic chemical equilibrium between activated and deactivated states. Copyright 2010 Elsevier Inc. All rights reserved.
