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PMID: 8981936 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.

The Journal of clinical investigation ·Vol. 98 ·No. 12 ·1996-12-15 ·Pages 2874-86

Balser JR, Nuss HB, Orias DW, Johns DC, Marban E, Tomaselli GF, Lawrence JH

Abstract

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.

MeSH Terms
Allosteric Regulation/physiology Anesthetics, Local/pharmacology Animals Cloning, Molecular Electrophysiology Lidocaine/pharmacology Microinjections Muscle, Skeletal/drug effects Mutagenesis, Site-Directed/genetics Oocytes/metabolism Patch-Clamp Techniques Rats Sodium Channels/drug effects,metabolism Xenopus
Chemicals
Anesthetics, Local Sodium Channels Lidocaine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Balser J R
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. jrbalser@welchlink.wlech.jhu.edu
Nuss H B
Orias D W
Johns D C
Marban E
Tomaselli G F
Lawrence J H
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI119116
Email
jrbalser@welchlink.wlech.jhu.edu
Published
1996-12-15
Pages
2874-86
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC507755
Subset
IM
Grants
NHLBI NIH HHS · K11 HL02639 · United States
NHLBI NIH HHS · R01 HL50411 · United States
NHLBI NIH HHS · R01 HL52768 · United States
External Links
PubMed source DOI: 10.1172/JCI119116 PMC Full Text View journal details
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