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Trendsetters

Ion Channelopathies and Heritable Epilepsy

Jeffrey L. Noebels

Developmental Neurogenetics Laboratory Dept. of Neurology Baylor College of Medicine One Baylor Plaza Houston, TX 77030
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.

Heinz Valtin

Editor, TRENDSETTERS

Inherited alterations of ion channels (ion channelopathies) in peripheral nerves that lead to bizarre neuromuscular disorders in experimental animal models, "somersaulting" pigeons, "stiff" goats, "shaking" flies, have been known for years. Now, not surprisingly, modifications of similar channels in the brain are being recognized as causes of hyperexcitability in the central nervous system and hence of an ancient phenotype, epilepsy. The bursting neuron is the cardinal feature of all seizure disorders, and ion channels hold the key to the phenotype. Mutations underlying inherited epilepsies fall into three major types: 1) those that alter the pore-forming channels responsible for ion fluxes, 2) those known to affect molecules that regulate the channels, and 3) mutations that do not appear to interact with channels but nevertheless interfere with channel function. Mutant mice, generated by accident or by design, provide excellent examples of such disorders.

First, several mutations have been identified in murine genes that encode the -subunit, the pore-forming region of ion channels. They include deletion of the Kv1.1 -subunit, leading to seizures similar to the "shaker" disorder in Drosophila (3), a point-mutation in a G protein-coupled inward rectifier, leading to the "weaver" mutation, and a mutation in the subunit of a P/Q-type calcium channel that results in "tottering" mice. Some of these mutations silence the channel, others may alter the ion selectivity of the channel, and still others may show little or no measurable effect on the channel itself.

Second, mutations exist in genes that determine the ß-subunits, which act as regulatory proteins. By interaction with -subunits, ß-subunits can alter both the density and behavior of ion channels, and, in the case of calcium channels, any ß-subunit can interact with any . Thus mutations that alter ß-proteins may affect many channel subtypes simultaneously. The "lethargic" mutation produces spike-wave epilepsy by deleting the region of the ß₄-subunit responsible for interaction between and ß (1). Without this site, a change could occur in all those calcium channels that incorporate the ß₄-subunit.

Finally, mutations exist that interfere with the action of transient channel modulators, such as protons or zinc. Such mutations may impede the rapidly reversible interactions of ion channels with the modulators, thereby favoring repetitive firing. The "slow wave epilepsy" mouse, for example, inherits a loss of the ubiquitous sodium/hydrogen exchanger, NHE1 (2), and the "mocha" gene encodes the -subunit of adaptin AP-3, which leads to, among other defects, impaired delivery of zinc to synaptic vesicles and hence to faulty modulation of potassium channels (Kantheti et al., Neuron 21: 111–122, 1998).

Just exactly how the various mutations cause epileptic seizures remains the ultimate riddle and one that almost certainly has no simple, single answer. Some channelopathies may alter the probability that a neuron will burst in response to normal input, and this fact alone may be sufficient when the cell is appropriately depolarized. Other channelopathies may act indirectly, by altering brain development, which itself depends on burst firing behavior. And, undoubtedly, there are other explanations. It is likely that the riddle will be solved eventually, but piecemeal, through discovery of other mutant channels and detailed analysis of their consequences.

References

1. Burgess, D. L., J. Jones, M. Meisler, and J. L. Noebels. Mutation of the Ca²⁺ channel ß-subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 88: 385–392, 1997.[Medline]
2. Cox, G. A., C. M. Lutz, C.-L. Yang, D. Biemesderfer, R. T. Bronson, A. Fu, P. S. Aronson, J. L. Noebels, and W. N. Frankel. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91: 139–148, 1997.[Medline]
3. Smart, S. L., V. Lopantsev, C. L. Zhang, C. A. Robbins, H. Wang, S. Y. Chiu, P. A. Schwartzkroin, A. Messing, and B. L. Tempel. Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron 20: 809–819, 1998.[Medline]

Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.

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