An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

Abstract

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABA A receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFSϩ). A novel mutation, R859C, in the Na v 1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFSϩ. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Na v 1.1 channel ␣ subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Na v 1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFSϩ sodium channel mutations, which have changes predicted to increase neuronal firing.

Nonfunctional Na V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

“…The computational model is similar to that already used in Cestèle et al (17); it is a modified version of that developed by Barela et al (30) and obtained using the NEURON 7.1 simulation environment. The model is based on the Hodgkin and Huxley formalism and implements a single-compartment neuronal soma containing Na V 1.1 Na + channels, delayed rectifier K + channels, and leak channels (SI Materials and Methods).…”

Impaired Inactivation Gate Stabilization Predicts Increased Persistent Current for an Epilepsy-AssociatedSCN1AMutation

“…For whole-cell simulations, the computational SCN1A model was expressed at a G Na_bar of 0.02 S/cm 2 . This corresponds to previously used sodium channel G Na_bar values between 0.01 and 0.2 S/cm 2 (Clancy and Kass, 2004;Spampanato et al, 2004a,b;Barela et al, 2006). For single-channel simulations, a single model SCN1A channel was expressed with a conductance (G Na ) of 17 pS.…”

“…The four previously reported SCN1A computational models were constructed using the published parameters (Clancy and Kass, 2004;Spampanato et al, 2004a,b;Barela et al, 2006). For simulation purposes, the G Na_bar of each model was reset to 0.02 S/cm 2 , the value used with our WT-SCN1A model.…”

“…The majority of efforts to simulate sodium channel behavior using computational models [including SCN1A (Spampanato et al, 2004a,b;Barela et al, 2006)] have used the classic HodgkinHuxley (HH) formalism (Hodgkin and Huxley, 1952). These equations define sodium permeability in terms of multiple identical gates operating independently.…”

Epileptic Channelopathies and Dysfunctional Excitability - From Gene Mutations to Novel Treatments

“…The mutation is therefore thought to enhance sodium channel function, thereby increasing neuronal excitability and predisposing to seizures. On the other hand, many of the characterized sodium channel mutations are found to cause attenuation of sodium current (Barela et al, 2006;Lossin et al, 2003;Sugawara et al, 2001). …”