The up-regulation of voltage-gated sodium channels subtypes coincides with an increased sodium current in hippocampal neuronal culture model

Prolongation of Action Potential Duration and QT Interval During Epilepsy Linked to Increased Contribution of Neuronal Sodium Channels to Cardiac Late Na + Current

“…These changes are strikingly similar to the findings of Guo et al 18 who reported a 16% increase and a negative shift of 7 mV in steady state activation of I Na in the hippocampus of epileptic rats. In brain, these gating alterations were mostly attributed to enhanced expression of nNa V s isoforms, Na V 1.1 and Na V 1.2.…”

“…Our results also raise the possibility that systemic changes in neurotransmitter levels or other signaling process during status epilepticus are acting as a trigger for overexpression of TTXsNa V s in both tissues and this contributes to cardiac arrhythmias observed during epilepsy in humans. 17,18 Based on our findings, we propose a new paradigm whereby an increased contribution of neuronal sodium channels alters the conduction properties of cardiomyocytes and the cardiac ventricular action potential duration both of which can contribute to the known risk of epileptic patients to SUDEP. …”

“…17,18,40 To verify if epilepsy was also associated with an increased expression of Na V 1.1 in the heart, we measured the amount of SCN1A and SCN5A cDNA, respectively, coding for the α-subunit of Na V 1.1 and Na V 1.5. Quantitative realtime RT-PCR experiments ( Figure 8A) using specific primers to each gene show a significant increase (49%) in expression of the Na V 1.1 cDNA in hearts from epileptic animals.…”

“…17,18 This enhanced expression of TTX-sensitive Na V s is thought to potentiate seizures by increasing I NaL and by also increasing excitability in brain cells. Missense mutations in Na V 1.1 and Na V 1.2 that increase I NaL amplitude [19][20][21] in hereditary epilepsy seem to confirm this hypothesis.…”

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

“…The pathogenesis of epilepsy or epileptogenesis is complex and has not been clearly defined, but it generally involves an imbalance between excitatory and inhibitory neurotransmission in multiple brain structures (11). Changes in the expression, localization, and function of a number of ion channels, including Nav1.2 (12,13), occur in the period following the initial acute seizures and may contribute to the resultant epileptogenesis, and at least some of these are mediated through altered PTMs (14). Nav channels, including Nav1.2, are also mutated in several forms of inherited epilepsy (15).…”