title: A common SCN5A variant alters the responsiveness of human sodium channels to class I antiarrhythmic agents.
abstract: BACKGROUND
  The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents.
  
  
  RESULTS
  The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) in [corrected] the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 microM) caused similar extent of tonic block reduction of sodium currents at -120 mV in WT and S524Y. Surprisingly, quinidine (20 microM) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22 degrees C (Ki: WT, 51.3 microM; S524Y, 20.3 microM). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (tau= 88.6 +/- 7.9 s vs 41.9 +/- 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37 degrees C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 microM), but not by mexiletine (100 microM).
  
  
  CONCLUSIONS
  A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response.
authors.affiliation: Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas 77030, USA.
authors.forename: Mossaab
authors.initials: M
authors.lastname: Shuraih
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Sohma
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Merkle
authors.forename: Erica
authors.initials: E
authors.lastname: Taylor
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.forename: Mehdi
authors.initials: M
authors.lastname: Razavi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D005424:Flecainide / Q000493:pharmacokinetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D008801:Mexiletine / Q000493:pharmacokinetics; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000493:pharmacokinetics; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008801:Mexiletine; D011802:Quinidine; D005424:Flecainide