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The S4 transmembrane alpha-helix in voltage-gated channels contains several regularly spaced basic amino acid residues that could be protonated and moved across the membrane electric field in response to membrane potential changes. The translocation of the charge-carrying S4 transduces membrane voltage to gating conformational changes of the channel, but how it is positioned and moved with respect to membrane lipid remains controversial. We found that hydrophilic and especially arginine and lysine substitution for L361 at the external end of S4 causes a large negative shift with shallowed slope of both activation and inactivation curves in Shaker K+ channels. Also, the macroscopic kinetics of activation and inactivation become much faster and barely voltage dependent, especially in the L361R mutant channel. These steady-state and kinetic data suggest that the replacement of one single hydrophobic residue, leucine, with arginine may profoundly destabilize the resting conformation of S4, which therefore takes a partially extruded position (partly activated position) at resting potentials (e.g. -120 mV). Consistently, the L361R point mutation gives rise to an extracellularly exposed R365C that is readily modified by external hydrophilic sulfhydryl-specific agents in the resting channel. Moreover, the extruded S4 in the L361R mutant channel could be retracted by strong hyperpolarizing potentials ( approximately -180 mV), from which the mutant channel is gated with slower kinetics but evidently stronger voltage dependence. We conclude that hydrophobic interaction involving a highly conserved residue at the top of S4 is crucial for properly securing the gating voltage sensor in the resting position and thus appropriate gating control of the voltage-gated channels.
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