Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons

Takashi Mori, Xilong Zhao, Yi Zuo, Gary L. Aistrup, Kiyonobu Nishikawa, William Marszalec, Jay Z. Yeh, Toshio Narahashi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Inhalational general anesthetics have recently been shown to inhibit neuronal nicotinic acetylcholine (ACh) receptors (nnAChRs) expressed in Xenopus laevis oocytes and in molluscan neurons. However, drug actions on these systems are not necessarily the same as those seen on native mammalian neurons. Thus, we analyzed the detailed mechanisms of action of halothane on nnAChRs using rat cortical neurons in long-term primary culture. Currents induced by applications of ACh via a U-tube system were recorded by the whole-cell, patch-clamp technique. ACh evoked two types of currents, α-bungarotoxin-sensitive, fast desensitizing (α7-type) currents and α-bungaro-toxin-insensitive, slowly desensitizing (α4β2-type) currents. Halothane suppressed α4β2-type currents more than α7-type currents with IC50 values of 105 and 552 μM, respectively. Halothane shifted the ACh dose-response curve for the α4β2-type currents in the direction of lower ACh concentrations and slowed its apparent rate of desensitization. The rate of recovery after washout from halothane block was much faster than the rate of recovery from ACh desensitization. Thus, the halothane block was not caused by receptor desensitization. Chlorisondamine, an irreversible open channel blocker for nnAChRs, caused a time-dependent block that was attenuated by halothane. These results could be accounted for by kinetic simulation based on a model in which halothane causes flickering block of open channels, as seen in muscle nAChRs. Halothane block of nnAChRs is deemed to play an important role in anesthesia via a direct action on the receptor and an indirect action to suppress transmitter release.

Original languageEnglish (US)
Pages (from-to)732-743
Number of pages12
JournalMolecular pharmacology
Volume59
Issue number4
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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