Journal article
Local anesthetic inhibition of a bacterial sodium channel
The Journal of general physiology, Vol.139(6), pp.507-516
06/2012
DOI: 10.1085/jgp.201210779
PMCID: PMC3362524
PMID: 22641643
Abstract
Recent structural breakthroughs with the voltage-gated sodium channel from
Arcobacter butzleri
suggest that such bacterial channels may provide a structural platform to advance the understanding of eukaryotic sodium channel gating and pharmacology. We therefore set out to determine whether compounds known to interact with eukaryotic Na
V
s could also inhibit the bacterial channel from
Bacillus halodurans
and NaChBac and whether they did so through similar mechanisms as in their eukaryotic homologues. The data show that the archetypal local anesthetic (LA) lidocaine inhibits resting NaChBac channels with a dissociation constant (
K
d
) of 260 µM, and channels displayed a left-shifted steady-state inactivation gating relationship in the presence of the drug. Extracellular application of QX-314 to expressed NaChBac channels had no effect on sodium current, whereas internal exposure via injection of a bolus of the quaternary derivative rapidly reduced sodium conductance, consistent with a hydrophilic cytoplasmic access pathway to an internal binding site. However, the neutral derivative benzocaine applied externally inhibited NaChBac channels, suggesting that hydrophobic pathways can also provide drug access to inhibit channels. Alternatively, ranolazine, a putative preopen state blocker of eukaryotic Na
V
s, displayed a
K
d
of 60 µM and left-shifted the NaChBac activation-voltage relationship. In each case, block enhanced entry into the inactivated state of the channel, an effect that is well described by a simple kinetic scheme. The data suggest that although significant differences exist, LA block of eukaryotic Na
V
s also occurs in bacterial sodium channels and that NaChBac shares pharmacological homology to the resting state of vertebrate Na
V
homologues.
Details
- Title: Subtitle
- Local anesthetic inhibition of a bacterial sodium channel
- Creators
- Sora Lee - Department of Anesthesiology, Pharmacology, and TherapeuticsSamuel J Goodchild - Department of Anesthesiology, Pharmacology, and TherapeuticsChristopher A Ahern - Department of Anesthesiology, Pharmacology, and Therapeutics
- Resource Type
- Journal article
- Publication Details
- The Journal of general physiology, Vol.139(6), pp.507-516
- DOI
- 10.1085/jgp.201210779
- PMID
- 22641643
- PMCID
- PMC3362524
- NLM abbreviation
- J Gen Physiol
- ISSN
- 0022-1295
- eISSN
- 1540-7748
- Publisher
- The Rockefeller University Press
- Alternative title
- NaChBac inhibition by local anesthetic compounds
- Language
- English
- Date published
- 06/2012
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070578902771
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