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A novel mechanism associated with idiopathic ventricular fibrillation (IVF) mutations R1232W and T1620M in human cardiac sodium channels.

Authors
  • Vilin, Y Y
  • Fujimoto, E
  • Ruben, P C
Type
Published Article
Journal
Pflügers Archiv : European journal of physiology
Publication Date
May 01, 2001
Volume
442
Issue
2
Pages
204–211
Identifiers
PMID: 11417215
Source
Medline
License
Unknown

Abstract

Two mutations associated with idiopathic ventricular fibrillation (IVF) are localized within extracellular loops between segments DIIIS1-S2 (R1232W) and DIVS3-S4 (T1620M) of the human cardiac sodium channel (hNav1.5) alpha-subunit. We studied wild-type hNav1.5 channels and hNav1.5 channels with the R1232W/T1620M double mutation expressed in Xenopus oocytes using the cell-attached macropatch technique. We demonstrate that these mutations destabilize the fast-inactivated state (described with a two-state first-order reaction model) by decreasing reaction valence, accelerating recovery, and slowing the onset of fast inactivation, collectively resulting in delayed decay of macroscopic currents. R1232W/T1620M mutations in hNav1.5 channels also significantly increase steady-state channel availability, indicating that mutated channels occupy the slow inactivated state less than hNav1.5 channels. Under the stress of repetitive depolarizing pulses, R1232W/T1620M channels demonstrate less use-dependent current reduction compared to wild-type channels. We propose that increased channel availability coupled with destabilized fast inactivation contributes to the pathological effect of R1232W/T1620M mutations, and leads to increased excitability of cardiac tissue in vivo.

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