title: Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man.
abstract: 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 beta1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal alpha-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 alpha-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.
authors: Departments of Applied Physiology and Neurology, University of Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1, D-89081, Ulm, Germany.
authors: A K
authors: AK
authors: Alekov
authors: M M
authors: MM
authors: Rahman
authors: N
authors: N
authors: Mitrovic
authors: F
authors: F
authors: Lehmann-Horn
authors: H
authors: H
authors: Lerche
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062553:NAV1.4 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062553:NAV1.4 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C106251:SCN4A protein, human; D015222:Sodium Channels