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J. Biol. Chem., Vol. 282, Issue 40, 29424-29430, October 5, 2007

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Design of a Specific Activator for Skeletal Muscle Sodium Channels Uncovers Channel Architecture^*

Lior Cohen, Nitza Ilan, Maya Gur, Walter Stühmer, 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 Department of Molecular Biology and Neuronal Signaling, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany

Gating modifiers of voltage-gated sodium channels (Na_vs) are important tools in neuroscience research and may have therapeutic potential in medicinal disorders. Analysis of the bioactive surface of the scorpion -toxin Css4 (from Centruroides suffusus suffusus) toward rat brain (rNa_v1.2a) and skeletal muscle (rNa_v1.4) channels using binding studies revealed commonality but also substantial differences, which were used to design a specific activator, Css4^{F14A/E15A/E28R}, of rNa_v1.4 expressed in Xenopus oocytes. The therapeutic potential of Css4^{F14A/E15A/E28R} was tested using an rNa_v1.4 mutant carrying the same mutation present in the genetic disorder hypokalemic periodic paralysis. The activator restored the impaired gating properties of the mutant channel expressed in oocytes, thus offering a tentative new means for treatment of neuromuscular disorders with reduced muscle excitability. Mutant double cycle analysis employing toxin residues involved in the construction of Css4^{F14A/E15A/E28R} and residues whose equivalents in the rat brain channel rNa_v1.2a were shown to affect Css4 binding revealed significant coupling energy (>1.3 kcal/mol) between F14A and E592A at Domain-2/voltage sensor segments 1–2 (D2/S1-S2), R27Q and E1251N at D3/SS2-S6, and E28R with both E650A at D2/S3-S4 and E1251N at D3/SS2-S6. These results show that despite the differences in interactions with the rat brain and skeletal muscle Na_vs, Css4 recognizes a similar region on both channel subtypes. Moreover, our data indicate that the S3-S4 loop of the voltage sensor module in Domain-2 is in very close proximity to the SS2-S6 segment of the pore module of Domain-3 in rNa_v1.4. This is the first experimental evidence that the inter-domain spatial organization of mammalian Na_vs resembles that of voltage-gated potassium channels.

Received for publication, June 6, 2007 , and in revised form, August 6, 2007.

^* This work was supported by German-Israeli Foundation for Scientific Research and Development Grant G-770-242.1/2002 (to D. G. and W. S.), 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 National Institutes of Health Grant 1 U01 NS058039-01 (to M. 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.

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

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. E-mail: mamgur{at}post.tau.ac.il.

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				L. Cohen, N. Lipstein, I. Karbat, N. Ilan, N. Gilles, R. Kahn, D. Gordon, and M. Gurevitz Miniaturization of Scorpion {beta}-Toxins Uncovers a Putative Ancestral Surface of Interaction with Voltage-gated Sodium Channels J. Biol. Chem., May 30, 2008; 283(22): 15169 - 15176. [Abstract] [Full Text] [PDF]

				L. Cohen, Y. Troub, M. Turkov, N. Gilles, N. Ilan, M. Benveniste, D. Gordon, and M. Gurevitz Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant "Insect-Selective" Toxins when Preconditioned Mol. Pharmacol., November 1, 2007; 72(5): 1220 - 1227. [Abstract] [Full Text] [PDF]