title: Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome.
abstract: OBJECTIVE
  In the type 3 long QT syndrome (LQT3), arrhythmia events tend to occur at rest or during sleep. One of the mutations, R1623Q, is located in the voltage sensor of the cardiac sodium channel (hH1), and patients with R1623Q mutation have been also reported to show bradycardia-dependent cardiac events. Although the mutant channel has been characterized by inactivation gating defects, the intrinsic mechanism(s) that might explain why arrhythmia attack is most prevalent at slower heart rates has not been investigated.
  
  
  METHODS
  cDNA encoding either the wild-type or the R1623Q mutant of hH1 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C.
  
  
  RESULTS
  A train of 50 depolarizing pulses from holding potentials (-120 and -80 mV) to -20 mV or a train of 50 action potential waveforms was applied at different frequencies. When using a rectangular waveform voltage clamp protocol, rate-dependent reduction of I(Na) was holding voltage-dependent but was not different between peak I(Na) and late I(Na). However, using the action potential clamp, preferential rate-dependent reduction of the phase 3 I(Na) was obvious as compared with peak I(Na). The discrepancy in the rate-dependent reduction between protocols was attributed to accelerated recovery from inactivation under non-equilibrium condition.
  
  
  CONCLUSIONS
  The rate dependency of phase 3 I(Na) under non-equilibrium gating is a novel mechanism to explain the enhanced rate-dependent QT-shortening in LQT3 patients. Our findings are important for genotype-phenotype correlations in LQT3 mutants as well as for understanding the function of S4 segment of domain IV region in the cardiac Na(+) channel.
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oginosawa
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Nagatomo
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Abe
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
mesh_terms: D000200:Action Potentials; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000378:metabolism / Q000503:physiopathology*; D009154:Mutation; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D015222:Sodium Channels