Desensitization of membrane-bound Torpedo acetylcholine receptor by amine noncompetitive antagonists and aliphatic alcohols: studies of (/sup 3/H)acetylcholine binding and /sup 22/Na/sup +/ ion fluxes
Measurements of the kinetics of binding of (/sup 3/H)acetylcholine ((/sup 3/H)AcCh) to membrane-bound nicotinic AcCh receptors from Torpedo electric tissue have been used to characterize the effects of amine and alcohol noncompetitive antagonists on receptor conformational equilibria. The receptor exists in interconvertible conformations distinguished by agonist binding affinity. The high-affinity receptor conformation stabilized by noncompetitive antagonists was characterized by (1) the rate constant (k/sub rec/) for receptor reisomerization upon removal of stabilizing ligand and (2) the rate constant (k/sub dis/) for dissociation of (/sup 3/H)AcCh-receptor complexes. On the basis of these criteria, the high-affinity receptor conformation stabilized by amine and alcohol noncompetitive blockers is the same as that stabilized by agonist. Histrionicotoxin (HTX) and adiphenine antagonized the conformational perturbation caused by proadifen, while mixtures of HTX and 2-propanol produced additive effects. Exposure to proadifen in the absence of agonist produced a reversible inhibition (desensitization) of the flux response, and recovery from desensitization occurred at the same rate as the reisomerization from the high-affinity receptor state. HTX, which did not cause desensitization of the flux response, reduced the desensitization by proadifen. These results are compatible with the hypothesis that certain noncompetitive antagonists modify receptor function by stabilizing the same high-affinity (desensitized) conformation that is stabilized by agonists, either as a consequence of binding to the allosteric site or by an alternate mechanism.
- Research Organization:
- Harvard Medical School, Boston, MA
- OSTI ID:
- 5779430
- Journal Information:
- Biochemistry; (United States), Vol. 23:18
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ACETYLCHOLINE
BIOCHEMICAL REACTION KINETICS
RECEPTORS
INHIBITION
AFFINITY
ALCOHOLS
AMINES
CATIONS
CELL MEMBRANES
FISHES
NERVE CELLS
SODIUM 22
SODIUM COMPOUNDS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ALKALI METAL COMPOUNDS
ALKALI METAL ISOTOPES
AMMONIUM COMPOUNDS
ANIMAL CELLS
ANIMALS
AQUATIC ORGANISMS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
CELL CONSTITUENTS
CHARGED PARTICLES
DRUGS
ESTERS
HYDROXY COMPOUNDS
IONS
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
LIGHT NUCLEI
MEMBRANES
NEUROREGULATORS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PARASYMPATHOMIMETICS
QUATERNARY COMPOUNDS
RADIOISOTOPES
REACTION KINETICS
SODIUM ISOTOPES
SOMATIC CELLS
VERTEBRATES
YEARS LIVING RADIOISOTOPES
550201* - Biochemistry- Tracer Techniques