title: A novel mechanism for LQT3 with 2:1 block: a pore-lining mutation in Nav1.5 significantly affects voltage-dependence of activation.
abstract: BACKGROUND
  SCN5A mutations that cause a gain of function in the cardiac voltage-gated sodium channel (Nav1.5) lead to long QT syndrome and a higher risk for sudden cardiac death.
  
  
  OBJECTIVE
  Here we functionally characterize the biophysical properties of the LQT3 variant, V411M, found in a newborn with a QT interval of 640 ms and 2:1 atrioventricular block.
  
  
  METHODS
  Whole cell patch clamp was performed on wild-type and V411M Nav1.5 channels stably expressed in human embryonic kidney cells.
  
  
  RESULTS
  V411M channels showed hyperpolarizing shifts in both the conductance-voltage (V(1/2) = -48.5 ± 2.2 mV vs. -40.4 ± 1.6 mV for wild-type) and inactivation-voltage (-95.6 ± 1.9 mV vs. -87.7 ± 1.7 mV) relationships, and a two-fold increase in late (sustained) sodium current during voltage ramp repolarizations. While neither mexiletine nor lidocaine exhibited potency differences between WT and V411M, or shortened the QTc in vivo, increased mutant block was observed with 10 μM flecainide (71.4 ± 3.0% vs. 60.3 ± 2.8%), in a voltage-dependent manner. Incorporation of V411M kinetics into atrial and ventricular action potential models reproduced prolonged action potential repolarization.
  
  
  CONCLUSIONS
  Our data suggest a novel mechanism for LQT3, a result of a hyperpolarizing shift in the steady state activation relationship and re-activation of Nav1.5 towards a higher open probability during repolarization of the cardiac action potential. This results in an increased number of open-activated sodium channels, and so drugs that bind this state preferentially are expected to shorten the QTc more than those that favour the inactivated state.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, B.C., V6T 1Z3, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Horne
authors.forename: Jodene
authors.initials: J
authors.lastname: Eldstrom
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.forename: David
authors.initials: D
authors.lastname: Fedida
mesh_terms: D054537:Atrioventricular Block / Q000235:genetics* / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels