Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man

Alexi K. Alekov, M. D. Masmudur Rahman, Nenad Mitrovic, Frank Lehmann-Horn, Holger Lerche

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Generalized epilepsy with febrile seizures-plus (GEFS+) is a benign Mendelian syndrome characterized by childhood-onset febrile and afebrile seizures. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the β1-subunit gene SCN1B and in GEFS+ type 2 two mutations within the neuronal α-subunit gene SCN1A. Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel α-subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the experiments revealed a pronounced enhancement of both fast and slow inactivation and a defect of channel activation for T685M compared to wild-type channels. Steady-state fast and slow inactivation curves were shifted in the hyperpolarizing direction, entry into slow inactivation was threefold accelerated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivation was the most obvious alteration in gating found for T685M, this might be the disease-causing mechanism for that mutation. In this case, the occurrence of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.

Original languageEnglish (US)
Pages (from-to)2171-2176
Number of pages6
JournalEuropean Journal of Neuroscience
Issue number11
StatePublished - 2001
Externally publishedYes


  • Febrile seizure
  • Genetics
  • Idiopathic generalized epilepsy
  • Ion channel
  • Patch clamp

ASJC Scopus subject areas

  • General Neuroscience


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