Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.
Time- and voltage-dependent local anesthetic effects on sodium (Na) currents are generally interpreted using modulated receptor models that require formation of drug-associated nonconducting states with high affinity for the inactivated channel. The availability of inactivation-deficient Na channels has enabled us to test this traditional view of the drug-channel interaction. Rat skeletal muscle Na channels were mutated in the III-IV linker to disable fast inactivation (F1304Q: FQ). Lidocaine accelerated the decay of whole-cell FQ currents in Xenopus oocytes, reestablishing the wild-type phenotype; peak inward current at -20 mV was blocked with an IC50 of 513 microM, while plateau current was blocked with an IC50 of only 74 microM (P < 0.005 vs. peak). In single-channel experiments, mean open time was unaltered and unitary current was only reduced at higher drug concentrations, suggesting that open-channel block does not explain the effect of lidocaine on FQ plateau current. We considered a simple model in which lidocaine reduced the free energy for inactivation, causing altered coupling between activation and inactivation. This model readily simulated macroscopic Na current kinetics over a range of lidocaine concentrations. Traditional modulated receptor models which did not modify coupling between gating processes could not reproduce the effects of lidocaine with rate constants constrained by single-channel data. Our results support a reinterpretation of local anesthetic action whereby lidocaine functions as an allosteric effector to enhance Na channel inactivation.
Balser
J R
JR
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. jrbalser@welchlink.wlech.jhu.edu
Nuss
H B
HB
Orias
D W
DW
Johns
D C
DC
Marban
E
E
Tomaselli
G F
GF
Lawrence
J H
JH
D000494:Allosteric Regulation / Q000502:physiology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003001:Cloning, Molecular; D004594:Electrophysiology; D008012:Lidocaine / Q000494:pharmacology*; D008845:Microinjections; D018482:Muscle, Skeletal / Q000187:drug effects; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D014981:Xenopus
D000779:Anesthetics, Local; D015222:Sodium Channels; D008012:Lidocaine