Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.
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.
Hanck
Dorothy A
DA
Cardiology (MC6094), University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637, USA. dhanck@uchicago.edu
Nikitina
Elena
E
McNulty
Megan M
MM
Fozzard
Harry A
HA
Lipkind
Gregory M
GM
Sheets
Michael F
MF
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
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