Conformational transitions of the nicotinic acetylcholine receptor as a model for anesthetic actions on ligand-gated ion channels: single and sequential mixing stopped-flow fluorescence studies.
(1) The effects of general anesthetic and nonanesthetic compounds on nicotinic acetylcholine receptor (nAcChoR) desensitization kinetics were characterized with stopped-flow fluorescence spectroscopy. (2) Anesthetics were found to increase the apparent rate of agonist-induced desensitization and shift the receptor equilibrium towards the desensitized state. (3) In contrast, nonanesthetics had little effect on either the apparent rate of desensitization or receptor equilibrium. (4) Octanol, but not isoflurane, decreases the rate of agonist dissociation from resting state nAcChoRs. (5) These results suggest that anesthetics alter nAcChoR desensitization kinetics by increasing either agonist binding affinity to the resting state or the channel opening probability.
Raines
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Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. raines@etherdome.mgh.harvard.edu
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D005453:Fluorescence; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D011487:Protein Conformation; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000187:drug effects*
D000777:Anesthetics; D008024:Ligands; D011976:Receptors, Muscarinic