Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.
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.Measurement of gating currents and concentration-dependent availability ... curves to determine the role of Phe1759 in coupling of drug binding to the gating changes.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.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.
Mesh Terms:
Anti-Arrhythmia Agents, Benzocaine, Binding Sites, Cell Line, Dose-Response Relationship, Drug, Humans, Ion Channel Gating, Lidocaine, Membrane Potentials, Models, Molecular, Molecular Structure, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Phenylalanine, Protein Conformation, Protein Structure, Tertiary, Sodium Channels, Transfection
Anti-Arrhythmia Agents, Benzocaine, Binding Sites, Cell Line, Dose-Response Relationship, Drug, Humans, Ion Channel Gating, Lidocaine, Membrane Potentials, Models, Molecular, Molecular Structure, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Phenylalanine, Protein Conformation, Protein Structure, Tertiary, Sodium Channels, Transfection
Circ. Res.
Date: Aug. 28, 2009
PubMed ID: 19661462
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