title: Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.
abstract: BACKGROUND
  Lidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in Na(V)1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block.
  
  
  OBJECTIVE
  Measurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes.
  
  
  RESULTS
  The measurements showed that replacement of Phe1759 with a nonaromatic residue permits clear separation of action of lidocaine and benzocaine into 2 components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4s in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed.
  
  
  CONCLUSIONS
  These 2 components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the 2 binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs.
authors: Cardiology (MC6094), University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637, USA. dhanck@uchicago.edu
authors: Dorothy A
authors: DA
authors: Hanck
authors: Elena
authors: E
authors: Nikitina
authors: Megan M
authors: MM
authors: McNulty
authors: Harry A
authors: HA
authors: Fozzard
authors: Gregory M
authors: GM
authors: Lipkind
authors: Michael F
authors: MF
authors: Sheets
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001566:Benzocaine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008012:Lidocaine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials; D008958:Models, Molecular; D015394:Molecular Structure; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010649:Phenylalanine; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D010649:Phenylalanine; D008012:Lidocaine; D001566:Benzocaine