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1 Dipartimento di Neurofisiopatologia, Istituto Neurologico Besta, Via Temolo 4, 20126 Milano, Italy
2 CNRS FRE 2738, Université de la Méditerranée, Laboratoire d'Ingénierie des Protéines, IFR Jean Roche, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
ß-Scorpion toxins specifically modulate the voltage dependence of sodium channel activation by acting through a voltage-sensor trapping model. We used mutagenesis, functional analysis and the action of ß-toxin as tools to investigate the existence and role in channel activation of molecular interactions between the charged residues of the S2, S3 and S4 segments in domain II of sodium channels. Mutating to arginine the acidic residues of the S2 and S3 transmembrane segments in domain II, or making charge-reversal mutation of the two outermost gating charges of the IIS4 voltage sensor, shifts the voltage dependence of channel activation to more positive potentials and enhances the effect of ß-scorpion toxin. Thus, mutations of acidic residues in IIS2 and IIS3 segments are able to promote voltage-sensor trapping in a way that is similar to the mutations of the arginines in the IIS4 segment. In order to disclose the network of interactions among acidic and basic residues we performed functional analysis of charge-inversion double mutants: our data suggest that the first arginine of the voltage sensor S4 in domain II (R850) interacts specifically with E805, D814 and E821 in the S2 and S3 segments, whereas the second arginine (R853) only interacts with D827 in the S3 segment. Our results suggest that the S2, S3 and S4 segments in domain II form a voltage-sensing structure, and that molecular interactions between the charged residues of this structure modulate the availability of the IIS4 voltage sensor for trapping by ß-toxins. They also provide unique insights into the molecular events that occur during channel activation, as well as into the structure of the channel.
(Received 24 June 2005;
accepted after revision 13 July 2005;
first published online 14 July 2005)
Corresponding author S. Cestèle: Laboratoire d'Ingénierie des Protéines, CNRS FRE 2738, Université de la Méditerranée, IFR Jean Roche, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France. Email: cestele.s{at}jean-roche.univ-mrs.fr
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