Inhibition of cation channel function at the nicotinic acethylcholine receptor from Torpedo: Agonist self-inhibition and anesthetic drugs
Modulation of the nicotinic acethylcholine receptor from Torpedo by cholinergic agonists, local anesthetics, and n-alkanols was studied using {sup 86}Rb{sup +} flux studies in sealed native Torpedo electroplaque membrane vesicles. Reliable concentration-response and kinetic data were obtained using manual ten sec filtration assays in vesicles partially blocked with alpha-bungarotoxin to remove spare receptors and quenched-flow assays to assess initial {sup 86}Rb{sup +} flux rates or the rate of drug-induced receptor inactivation. Concentration response relationships for the agonists acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, and (-)-nicotine are all bell-shape due to stimulation of cation channel opening at low concentrations and inhibition of channels at higher concentrations. The rate of agonist-induced fast desensitization (k{sub d}) increases with (acetylcholine) in parallel with channel activation, suggesting that desensitization proceeds from the open state and/or states in rapid equilibrium with it. At self-inhibitory acetylcholine concentrations, a new rapid inactivation (rate = k{sub f}) is observed before fast desensitization. The rate and extent of rapid inactivation is compatible with bimolecular association between acethylcholine and inhibitory site with K{sub B} = 40 mM.
- Research Organization:
- Harvard Univ., Boston, MA (USA)
- OSTI ID:
- 6172540
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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ACETYLCHOLINE
RECEPTORS
ANESTHETICS
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MEMBRANE TRANSPORT
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DOSE-RESPONSE RELATIONSHIPS
FISHES
RUBIDIUM 86
TRACER TECHNIQUES
ALKALI METAL ISOTOPES
AMINES
AMMONIUM COMPOUNDS
ANIMALS
AQUATIC ORGANISMS
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BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
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DAYS LIVING RADIOISOTOPES
DRUGS
ESTERS
INTERMEDIATE MASS NUCLEI
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ISOMERIC TRANSITION ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
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MEMBRANES
MINUTES LIVING RADIOISOTOPES
NEUROREGULATORS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PARASYMPATHOMIMETICS
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550201* - Biochemistry- Tracer Techniques