Abstract
The activation of voltage-sensors, upon depolarization, leads to the opening of pore gates in a voltage-dependent sodium channel. To elucidate the molecular principles underlying this conformational coupling, we have investigated a putative gating interface in domain III of the sodium channel using voltage-clamp fluorimetry and tryptophan-scanning mutagenesis. Most mutations have similar energetic effects on voltage-sensor activation and pore opening. However, several mutants stabilized the activated voltage-sensor while concurrently destabilizing the open pore. When these mutants were mapped onto a homology model of the sodium channel, most of them were localized to hinge regions of the gating interface. Our analysis shows that these residues are involved in energetic coupling of the voltage-sensor and the pore when both are in the resting or activated conformation. These results support the notion that electromechanical coupling in a voltage-dependent ion channel involves movement of rigid helical segments connected by elastic hinges.Support: National Institutes of Health, AHA and Shaw Scientific Award.
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