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J. Biol. Chem., Vol. 281, Issue 29, 20326-20337, July 21, 2006

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Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a -Scorpion Toxin Solely in Na_v1.6 Channel

SIGNIFICANCE IN MICE PURKINJE NEURONS^*

Emanuele Schiavon¹², Tiziana Sacco¹, Rita Restano Cassulini², Georgina Gurrola^¶, Filippo Tempia, Lourival D. Possani^¶, and Enzo Wanke^¶3

From the Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan 20126, Italy, the Department of Neurosciences, University of Turin, Turin 10126, Italy, and the ^¶Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca 62271, Morelos, Mexico

Resurgent currents are functionally crucial in sustaining the high frequency firing of cerebellar Purkinje neurons expressing Na_v1.6 channels. -Scorpion toxins, such as CssIV, induce a left shift in the voltage-dependent activation of Na_v1.2 channels by "trapping" the IIS4 voltage sensor segment. We found that the dangerous Cn2 -scorpion peptide induces both the left shift voltage-dependent activation and a transient resurgent current only in human Na_v1.6 channels (among 1.1-1.7), whereas CssIV did not induce the resurgent current. Cn2 also produced both actions in mouse Purkinje cells. These findings suggest that only distinct -toxins produce resurgent currents. We suggest that the novel and unique selectivity of Cn2 could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease.

Received for publication, January 19, 2006 , and in revised form, May 11, 2006.

^* This study was supported in part by Italian Ministero dell'Università e della Ricerca Scientifica e Tecnologica Grants MIUR-PRIN2003-2005-2001055320 and 2003052919, MIUR-FIRB2001-RBNE01XMP4-002, and MIUR-FISR2001 0300179 and the Università di Milano-Bicocca (to E. W.). It also was supported by the National Council of Science and Technology (Mexican Government Grant 40251-Q) and by Direción General de Asuntos de Personal Académico Grant IN206003 of the National Autonomous University of Mexico (to L. D. P.). 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 These two authors contributed equally to this work.

² Ph.D. student of Physiology at the Department of Biotechnologies and Biosciences of the University of Milano-Bicocca.

³ To whom correspondence should be addressed: Dipartimento di Biotecnologie e Bioscience, Università di Milano-Bicocca, Piazza della Scienza, 2U3, 20126 Milan, Italy. E-mail: enzo.wanke{at}unimib.it.

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