title: A thermoprotective role of the sodium channel β1 subunit is lost with the β1 (C121W) mutation.
abstract: OBJECTIVE
  A mutation in the β(1) subunit of the voltage-gated sodium (Na(V)) channel, β(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 β(1) (C121W) may be exacerbated by elevated temperature. We investigated the putative mechanism underlying seizure generation by the β(1) (C121W) mutation with elevated temperature.
  
  
  METHODS
  Whole-cell voltage clamp experiments were performed at 22 and 34°C using Chinese Hamster Ovary (CHO) cells expressing the α subunit of neuronal Na(V) 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) β(1) subunit, or Na(V) 1.2 plus β(1) (C121W).
  
  
  RESULTS
  Our results suggest WT β(1) is protective against increased channel excitability induced by elevated temperature; protection is lost in the absence of WT β(1) or with expression of β(1) (C121W). At 34°C, Na(V) 1.2 + β(1) (C121W) channel excitability increased compared to NaV1.2 + WT β(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.
  
  
  CONCLUSIONS
  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 β(1) (C121W): increased channel excitability at elevated temperature.
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Csilla
authors.initials: C
authors.lastname: Egri
authors.forename: Yuriy Y
authors.initials: YY
authors.lastname: Vilin
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ruben
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000235:genetics; D060467:Disease Resistance / Q000235:genetics; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006358:Hot Temperature / Q000009:adverse effects; D008564:Membrane Potentials / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics; D051381:Rats; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568253:Scn2A protein, rat; D015222:Sodium Channels