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J. Biol. Chem., Vol. 281, Issue 30, 21332-21344, July 28, 2006

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Structure and Function of the Voltage Sensor of Sodium Channels Probed by a -Scorpion Toxin^*

Sandrine Cestèle, Vladimir Yarov-Yarovoy, Yusheng Qu¹, François Sampieri, Todd Scheuer, and William A. Catterall²

From the Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280 and the Facultéde Medecine Nord, Université de la Mediterranée, Bd. Pierre Dramard, 13916 Marseille Cedex 20, France

Voltage sensing by voltage-gated sodium channels determines the electrical excitability of cells, but the molecular mechanism is unknown. -Scorpion toxins bind specifically to neurotoxin receptor site 4 and induce a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism. Kinetic analysis showed that -scorpion toxin binds to the resting state, and subsequently the bound toxin traps the voltage sensor in the activated state in a voltage-dependent but concentration-independent manner. The rate of voltage sensor trapping can be fit by a two-step model, in which the first step is voltage-dependent and correlates with the outward gating movement of the IIS4 segment, whereas the second step is voltage-independent and results in shifted voltage dependence of activation of the channel. Mutations of Glu⁷⁷⁹ in extracellular loop IIS1-S2 and both Glu⁸³⁷ and Leu⁸⁴⁰ in extracellular loop IIS3-S4 reduce the binding affinity of -scorpion toxin. Mutations of positively charged and hydrophobic amino acid residues in the IIS4 segment do not affect -scorpion toxin binding but alter voltage dependence of activation and enhance -scorpion toxin action. Structural modeling with the Rosetta algorithm yielded a three-dimensional model of the toxin-receptor complex with the IIS4 voltage sensor at the extracellular surface. Our results provide mechanistic and structural insight into the voltage sensor-trapping mode of scorpion toxin action, define the position of the voltage sensor in the resting state of the sodium channel, and favor voltage-sensing models in which the S4 segment spans the membrane in both resting and activated states.

Received for publication, April 20, 2006 , and in revised form, May 4, 2006.

^* The work at the University of Washington was supported by National Institutes of Health Research Grants R01 NS15751 (to W. A. C.) and MH67625 (to V. Y.-Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Present address: Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799.

² To whom correspondence should be addressed. Tel.: 206-543-1925; Fax: 206-543-3882; E-mail: wcatt{at}u.washington.edu.

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