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J. Biol. Chem., Vol. 281, Issue 30, 20673-20679, July 28, 2006

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Direct Evidence That Receptor Site-4 of Sodium Channel Gating Modifiers Is Not Dipped in the Phospholipid Bilayer of Neuronal Membranes^*

Lior Cohen, Nicolas Gilles, Izhar Karbat, Nitza Ilan, Dalia Gordon¹, and Michael Gurevitz²

From the Department of Plant Sciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel and the Commissariat à l'Energie Atomique, Department d'Ingenierie et d'Etudes des Proteines, C.E. Saclay, F-91191 Gif Sur Yvette Cedex, France

In a recent note to Nature, R. MacKinnon has raised the possibility that potassium channel gating modifiers are able to partition in the phospholipid bilayer of neuronal membranes and that by increasing their partial concentration adjacent to their receptor, they affect channel function with apparent high affinity (Lee and MacKinnon (2004) Nature 430, 232–235). This suggestion was adopted by Smith et al. (Smith, J. J., Alphy, S., Seibert, A. L., and Blumenthal, K. M. (2005) J. Biol. Chem. 280, 11127–11133), who analyzed the partitioning of sodium channel modifiers in liposomes. They found that certain modifiers were able to partition in these artificial membranes, and on this basis, they have extrapolated that scorpion -toxins interact with their channel receptor in a similar mechanism as that proposed by MacKinnon. Since this hypothesis has actually raised a new conception, we examined it in binding assays using a number of pharmacologically distinct scorpion -toxins and insect and mammalian neuronal membrane preparations, as well as by analyzing the rate by which the toxin effect on gating of Drosophila DmNa_v1 and rat brain rNa_v1.2a develops. We show that in general, scorpion -toxins do not partition in neuronal membranes and that in the case in which a depressant -toxin partitions in insect neuronal membranes, this partitioning is unrelated to its interaction with the receptor site and the effect on the gating properties of the sodium channel. These results negate the hypothesis that the high affinity of -toxins for sodium channels is gained by their ability to partition in the phospholipid bilayer and clearly indicate that the receptor site for scorpion -toxins is accessible to the extracellular solvent.

Received for publication, April 4, 2006 , and in revised form, May 9, 2006.

^* This research was supported by United States-Israel Binational Agricultural Research and Development Grant IS-3480-03 (to M. G. and D. G.); by Israeli Science Foundation, Grants 733/01 (to M. G.) and 1008/05 (to D. G.); and by the German-Israeli Foundation for Scientific Research and Development Grant G-770-242.1/2002 (to D. G.). 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.

¹ To whom correspondence may be addressed. Tel.: 972-3-6409844; Fax: 972-3-6406100; E-mail: dgordon{at}post.tau.ac.il. ² To whom correspondence may be addressed. Tel.: 972-3-6409844; Fax: 972-3-6406100; E-mail: mamgur{at}post.tau.ac.il.

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