title: A novel mechanism associated with idiopathic ventricular fibrillation (IVF) mutations R1232W and T1620M in human cardiac sodium channels.
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.
authors: Department of Biology, Utah State University, Logan, UT 84322, USA.
authors: Y Y
authors: YY
authors: Vilin
authors: E
authors: E
authors: Fujimoto
authors: P C
authors: PC
authors: Ruben
mesh_terms: D000818:Animals; D004594:Electrophysiology; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D009154:Mutation / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels