Subunit-dependent Inhibition of Human Neuronal Nicotinic Acetylcholine Receptors and Other Ligand-gated Ion Channels by Dissociative Anesthetics Ketamine and Dizocilpine

  title={Subunit-dependent Inhibition of Human Neuronal Nicotinic Acetylcholine Receptors and Other Ligand-gated Ion Channels by Dissociative Anesthetics Ketamine and Dizocilpine},
  author={Tomohiro Yamakura and Laura E. Chavez-Noriega and R. Adron Harris},
Background: The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia. Methods: Heteromeric human neuronal nicotinic… 
A Role for Neuronal Nicotinic Acetylcholine Receptors in Dopamine-Mediated Behaviors and the Hypnotic Response to Anesthetics: A Dissertation
It is found that DHβE, a selective antagonist for α4β2* nAChRs, induced reversible and robust motor dysfunction characterized by hypolocomotion, akinesia, catalepsy, tremor, and clasping in Leu9’Ala but not WT mice, and α4 knockout mice were less sensitive to the hypnotic effects of ketamine but α6 KO were more sensitive.
Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAA Receptors Containing α6 and δ Subunits
It is shown that at anesthetically relevant concentrations, ketamine, but not PCP, modulates α6β2δ and α6 β3δ receptors, and at higher concentrations,ketamine directly activates these GABAA receptors.
Effects of Gaseous Anesthetics Nitrous Oxide and Xenon on Ligand-gated Ion Channels: Comparison with Isoflurane and Ethanol
The results suggest that NMDA receptors and nACh receptors composed of &bgr;2 subunits are likely targets for nitrous oxide and xenon, which are distinct from that of isoflurane or ethanol.
The Anesthetic Mechanism of Urethane: The Effects on Neurotransmitter-Gated Ion Channels
At concentrations close to anesthetic 50% effective concentration, urethane had modest effects on all channels tested, suggesting the lack of a single predominant target for its action, which may account for its usefulness as a veterinary anesthetic.
Single Amino Acid Residue in the Extracellular Portion of Transmembrane Segment 2 in the Nicotinic &agr;7 Acetylcholine Receptor Modulates Sensitivity to Ketamine
Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the &agr;7 nicotinic receptor and sensitivity to inhibition inThe 5HT3A receptor.
Effect of N-methyl-d-aspartate Receptor &egr;1 Subunit Gene Disruption of the Action of General Anesthetic Drugs in Mice
Findings show consistently that the NMDA receptor &egr;1 subunit mediates nitrous oxide but not sevoflurane anesthesia.
Inhibitory effects of intravenous anaesthetic agents on K+-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca2+ channels and GABAA receptors
A range of anaesthetic agents at clinically achievable concentrations inhibit glutamate release and this inhibition of release appears to be due mainly to direct inhibition of P/Q-type VSCCs, although activation of the GABAA receptor plays a role in this response.
Actions of anesthetics on excitatory transmitter-gated channels.
Excitatory transmitter-gated receptors are found in three gene families: the glutamate ionotropic receptors, the Cys-loop receptor family (nicotinic and 5HT3), and the purinergic (P2X) receptors.
Droperidol Inhibits GABAA and Neuronal Nicotinic Receptor Activation
The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia.


Human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes predict efficacy of halogenated compounds that disobey the Meyer-Overton rule.
The in vivo potency and effectiveness of volatile anesthetic and nonimmobilizer compounds were consistent with their actions on hnAChRs expressed in a recombinant expression system, suggesting a potential participation of these receptors in the mechanisms of anesthesia.
Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels.
  • J. E. Huettner, B. Bean
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
MK-801 greatly reduced the channel activity elicited by application of N-Me-D-Asp but did not significantly alter the predominant unitary conductance, and the mean channel open time was reduced by MK-801 in a dose-dependent manner.
The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels.
The results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801 and were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors.
Different sensitivities of NMDA receptor channel subtypes to non-competitive antagonists.
The replacement by glutamine or arginine of the conserved asparagine residue in segment M2 of the epsilon 2 and zeta 1 NMDA receptor channel subunits reduced the sensitivities to PCP, ketamine and SKF-10,047, though to different extents.
MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys.
The findings of this study offer further support for the hypothesis that certain behavioral effects of PCP-like drugs may result from a reduction of neurotransmission at excitatory synapses utilizing NMDA-preferring receptors.
MK‐801 inhibition of nicotinic acetylcholine receptor channels
The relative potency of tricyclic compounds like MK‐801 for various neurotransmitter systems points out that the pharmacologic action of these drugs could involve complicated interactions in vivo.
α4‐β2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs
The much greater relative nicotine sensitivity of the neuronal subtypes as compared with muscle receptors illustrates their potential to mediate the psychoactive and addictive effects of nicotine, but it does not appear that the differences in relative nicotinic sensitivity among the neuronal receptors themselves can be used as a simple discriminative tool in neuronal tissue.
Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine.
In the presence of ketamine, peak inward currents evoked by repeated applications of NMDA, L-Asp, or L-Glu progressively declined to a steady-state level of block (use-dependent block), and recovery from blockade, like development of blockade, was use dependent.
Human neuronal nicotinic receptors