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J. Biol. Chem., Vol. 280, Issue 18, 17678-17686, May 6, 2005

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Specific Kinetic Alterations of Human Ca_V2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma^*

Angelita Tottene, Francesca Pivotto, Tommaso Fellin, Tiziana Cesetti, Arn M. J. M. van den Maagdenberg¶||, and Daniela Pietrobon**

From the Department of Biomedical Sciences, University of Padova, CNR Institute of Neuroscience, Viale G. Colombo 3, 35121 Padova, Italy, the ^¶Department of Human Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands, and the ^||Department of Neurology, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands

Mutation S218L in the Ca_V2.1 ₁ subunit of P/Q-type Ca²⁺ channels produces a severe clinical phenotype in which typical attacks of familial hemiplegic migraine (FHM) triggered by minor head trauma are followed, after a lucid interval, by deep (even fatal) coma and long lasting severe cerebral edema. We investigated the functional consequences of this mutation on human Ca_V2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca_V2.1 ₁^–/– mice by combining single channel and whole cell patch clamp recordings. Mutation S218L produced a shift to lower voltages of the single channel activation curve and a consequent increase of both single channel and whole cell Ba²⁺ influx in both neurons and human embryonic kidney 293 cells. Compared with the other FHM-1 mutants, the S218L shows one of the largest gains of function, especially for small depolarizations, which are insufficient to open the wild-type channel. S218L channels open at voltages close to the resting potential of many neurons. Moreover, the S218L mutation has unique effects on the kinetics of inactivation of the channel because it introduces a large component of current that inactivates very slowly, and it increases the rate of recovery from inactivation. During long depolarizations at voltages that are attained during cortical spreading depression, the extent of inactivation of the S218L channel is considerably smaller than that of the wild-type channel. We discuss how the unique combination of a particularly slow inactivation during cortical spreading depression and a particularly low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma.

Received for publication, January 31, 2005 , and in revised form, February 25, 2005.

^* This work was supported by Telethon-Italy (Grant E1297), the Italian Ministry of University and Research (Grants Prin2003, FIRB2002, St-L449/97, Fondo Integrativo Speciale per la Ricerca), and the European Community (EUROHEAD Grant LSHM-CT-2004-504837). 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 39-49-827-6052; Fax: 39-49-827-6049; E-mail: daniela.pietrobon{at}unipd.it.

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