Specific Kinetic Alterations of Human CaV2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma

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

doi:10.1074/jbc.m501110200

Daniela Pietrobon, Francesca Pivotto + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m501110200

Copy DOI

Abstract

Mutation S218L in the Ca(V)2.1 alpha(1) subunit of P/Q-type Ca(2+) 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(V)2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca(V)2.1 alpha(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 Ba(2+) 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.

Highlights

Mutation S218L in the CaV2.1 ␣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 coma and long lasting severe cerebral edema
Mutation S218L in the IS4-IS5 loop of the CaV2.1 ␣1 subunit produces a severe clinical phenotype in which typical attacks of FHM triggered by minor head trauma are frequently followed, after a lucid interval, by deep coma or profound stupor, high fever, and long lasting severe cerebral edema
To investigate whether the functional consequences of mutation S218L were or were not similar to those of typical FHM-1 mutations, first of all, we performed cell-attached single channel recordings on HEK293 cells transfected with human CaV2.1 ␣1 subunits containing mutation S218L and human ␣2b␦ and ␤2e subunits and measured i and po of the mutant channels as a function of voltage

Summary

Introduction

Mutation S218L in the CaV2.1 ␣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. A consistent effect of FHM-1 mutations was to increase Ca2ϩ influx through single human CaV2.1 channels in a broad voltage range as a consequence of an increased channel open probability mainly because of a shift to lower voltages of channel activation [13, 14]. Mutation S218L in the IS4-IS5 loop of the CaV2.1 ␣1 subunit produces a severe clinical phenotype in which typical attacks of FHM triggered by minor head trauma are frequently followed, after a lucid interval, by deep (even fatal) coma or profound stupor, high fever, and long lasting severe cerebral edema

Methods

Results

Conclusion