The TiPS lecture the nicotinic acetylcholine receptor: an allosteric protein prototype of ligand-gated ion channels

1990 ◽  
Vol 11 (12) ◽  
pp. 485-492 ◽  
Author(s):  
Jean-Pierre Changeux
Keyword(s):  
Ion Channels ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Allosteric Protein ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

General Anesthetics Modify the Kinetics of Nicotinic Acetylcholine Receptor Desensitization at Clinically Relevant Concentrations 

1995 ◽  
Vol 82 (1) ◽  
pp. 276-287 ◽  
Author(s):  
Douglas E. Raines ◽  
Saffron E. Rankin ◽  
Keith W. Miller
Keyword(s):  
Ion Channels ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Electric Organ ◽  
General Anesthetics ◽  
Nicotinic Acetylcholine ◽  
Rate Processes ◽  
Kinetics Of ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Background General anesthetics are thought to induce anesthesia through their actions on ligand-gated ion channels. One such channel, the nicotinic acetylcholine receptor (nAcChoR), can be found in different subtypes in the central nervous system and at the periphery in the neuromuscular junction. The latter subtype of the nAcChoR is a useful model for examining interactions between general anesthetics and ligand-gated ion channels, because it can be isolated and purified in sufficient quantities to allow for biophysical and biochemical studies. This study examines the actions of general anesthetics on agonist-induced conversion of the nAcChoR to inactive desensitized conformational states. Methods Nicotinic acetylcholine receptor membranes were purified from the electric organ of Torpedo nobiliana. Agonist-induced desensitization was characterized from the time-dependent increase in fluorescence intensity that results from the binding of the fluorescent acetylcholine analog, Dns-C6-Cho, to the nAcChoR. Results Mixing Dns-C6-Cho with nAcChoR-rich membranes results in an increase in fluorescence that is characterized by four rate processes. Concentrations of isoflurane and butanol, which range from subclinical to toxic increase the rates of the third and fourth components of fluorescence, corresponding to fast and slow desensitization, respectively. At concentrations that are twice their EC50s for anesthesia, isoflurane, butanol, chloroform, methanol, and cyclopentanemethanol increase the apparent rates of fast and slow desensitization by an average of 92 +/- 22% and 108 +/- 22%, respectively. Conclusions The concentration range over which general anesthetics modify the kinetics of nAcChoR desensitization is similar to those reported for anesthetic actions on the GABAA receptor. Thus, the nAcChoR, like other members of this superfamily, is a sensitive target of general anesthetics.

Anesthetic and Nonanesthetic Halogenated Volatile Compounds Have Dissimilar Activities on Nicotinic Acetylcholine Receptor Desensitization Kinetics

1996 ◽  
Vol 84 (3) ◽  
pp. 663-671 ◽  
Author(s):  
Douglas E. Raines
Keyword(s):  
Ion Channels ◽  
General Anesthesia ◽  
Volatile Compounds ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Mechanistic Model ◽  
Nicotinic Acetylcholine ◽  
Gaba A ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Background The Meyer-Overton rule predicts that an anesthetic's potency will correlate with its oil solubility. A group of halogenated volatile compounds that disobey this rule has been characterized. These compounds do not induce anesthesia in rats at partial pressures exceeding those predicted by the Meyer-Overton rule to be anesthetic. The observation that potentiation of GABA(A) receptor responses by anesthetic and nonanesthetic halogenated volatile compounds correlates with their abilities to induce general anesthesia suggests that this receptor is involved in the mechanism of general anesthesia. However, the GABA(A) receptor is only one member of a superfamily of structurally similar ligand-gated ion channels. This study compares the actions of both anesthetic and nonanesthetic halogenated volatile compounds on another member of this super family of receptors, the nicotinic acetylcholine receptor (nAcChoR). Methods The actions of both anesthetic and nonanesthetic compounds on desensitization kinetics were characterized from the time-dependent binding of the fluorescent acetylcholine analogue, Dns-C6-Cho, to the nAcChoR. Results At concentrations predicted by the Meyer-Overton rule to be equianesthetic, the anesthetics isoflurane and enflurane were significantly more effective than the nonanesthetics 1,2-dichlorohexafluorocyclobutane and 2, 3-dichlorooctafluorobutane in enhancing the fraction of receptors preexisting in the slow desensitized state and increasing the apparent rates of agonist-induced fast and slow desensitization. Conclusions The potencies with which anesthetic and nonanesthetic compounds enhance desensitization kinetics in the nAcChoR parallel their in vivo anesthetic potencies. These results support the use of desensitization of the nAcChoR as a mechanistic model for studies of general anesthesia and suggest that an insensitivity to nonanesthetic compounds may be a feature common to members of the superfamily of ligand-gated ion channels.

Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels

2001 ◽  
Vol 95 (2) ◽  
pp. 470-477 ◽  
Author(s):  
Douglas E. Raines ◽  
Robert J. Claycomb ◽  
Michaela Scheller ◽  
Stuart A. Forman
Keyword(s):  
Ion Channels ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Gaba A ◽  
Agonist Affinity ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Background Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. Methods Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. Results Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. Conclusions Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.

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