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Electrostatic Model of S4 Motion in Voltage-Gated Ion Channels

Harold Lecar ^*, H. Peter Larsson  and Michael Grabe 

^* Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California; Neurological Sciences Institute, Oregon Health Sciences University, Beaverton, Oregon; and Howard Hughes Medical Institute, University of California, San Francisco, California

Correspondence: Address reprint requests to Harold Lecar, Dept. of Cell and Molecular Biology, 134 LSA, MC# 3200, University of California at Berkeley, Berkeley, CA 94720. E-mail: hlecar{at}uclink4.berkeley.edu.

The S4 transmembrane domain of the family of voltage-gated ion channels is generally thought to be the voltage sensor, whose translocation by an applied electric field produces the gating current. Experiments on hSkMI Na⁺ channels and both Shaker and EAG K⁺ channels indicate which S4 residues cross the membrane-solution interface during activation gating. Using this structural information, we derive the steady-state properties of gating-charge transfer for wild-type and mutant Shaker K⁺ channels. Assuming that the energetics of gating is dominated by electrostatic forces between S4 charges and countercharges on neighboring transmembrane domains, we calculate the total energy as a function of transmembrane displacement and twist of the S4 domain. The resulting electrostatic energy surface exhibits a series of deep energy minima, corresponding to the transition states of the gating process. The steady-state gating-charge distribution is then given by a Boltzmann distribution among the transition states. The resulting gating-charge distributions are compared to experimental results on wild-type and charge-neutralized mutants of the Shaker K⁺ channel.

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