TY - JOUR
T1 - Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons
AU - Mori, Takashi
AU - Zhao, Xilong
AU - Zuo, Yi
AU - Aistrup, Gary L.
AU - Nishikawa, Kiyonobu
AU - Marszalec, William
AU - Yeh, Jay Z.
AU - Narahashi, Toshio
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1124/mol.59.4.732
DO - 10.1124/mol.59.4.732
M3 - Article
C2 - 11259617
AN - SCOPUS:0035057449
VL - 59
SP - 732
EP - 743
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 4
ER -