A thermoprotective role of the sodium channel beta(1) subunit is lost with the beta(1)(C121W) mutation

作者：Egri Csilla; Vilin Yuriy Y; Ruben Peter C^*

来源：Epilepsia, 2012, 53(3): 494-505.

DOI：10.1111/j.1528-1167.2011.03389.x

• Febrile seizures
• GEFS(+)
• Patch clamp
• Temperature

Purpose: A mutation in the beta(1) subunit of the voltage-gated sodium (Na-V) channel, beta(1)(C121W), causes genetic epilepsy with febrile seizures plus (GEFS(+)), a pediatric syndrome in which febrile seizures are the predominant phenotype. Previous studies of molecular mechanisms underlying neuronal hyperexcitability caused by this mutation were conducted at room temperature. The prevalence of seizures during febrile states in patients with GEFS(+), however, suggests that the phenotypic consequence of beta(1)(C121W) may be exacerbated by elevated temperature. We investigated the putative mechanism underlying seizure generation by the beta(1)(C121W) mutation with elevated temperature. %26lt;br%26gt;Methods: Whole-cell voltage clamp experiments were performed at 22 and 34 degrees C using Chinese Hamster Ovary (CHO) cells expressing the a subunit of neuronal NaV channel isoform, Na(V)1.2. Voltage-dependent properties were recorded from CHO cells expressing either Na(V)1.2 alone, Na(V)1.2 plus wild-type (WT) beta(1) subunit, or Na(V)1.2 plus beta(1)(C121W). %26lt;br%26gt;Key Findings: Our results suggest WT beta(1) is protective against increased channel excitability induced by elevated temperature; protection is lost in the absence of WT beta(1) or with expression of beta(1)(C121W). At 34 degrees C, Na(V)1.2 + beta(1)(C121W) channel excitability increased compared to Na(V)1.2 + WT beta(1) by the following mechanisms: decreased use-dependent inactivation, increased persistent current and window current, and delayed onset of, and accelerated recovery from, fast inactivation. %26lt;br%26gt;Significance: Temperature-dependent changes found in our study are consistent with increased neuronal excitability of GEFS(+) patients harboring C121W. These results suggest a novel seizure-causing mechanism for beta(1)(C121W): increased channel excitability at elevated temperature.

• 出版日期2012-3