Agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action

Journal Article · Tue May 19 04:00:00 EDT 1987 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00384a023· OSTI ID:5768491

Forman, S A; Firestone, L L; Miller, K W

Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring /sup 86/Rb/sup +/ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: (1) integrated net ion efflux (in 10 s) from untreated vesicles, (2) integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with ..cap alpha..-bungarotoxin, and (3) initial rates of efflux (5-100 ms) from vesicles that were partially blocked with ..cap alpha..-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10/sup 8/-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum /sup 86/Rb/sup +/ efflux by 50% (K/sub B/ values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, K/sub B/ values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times K/sub B/ did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. The authors conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

• Research Organization: Harvard Univ., Cambridge, MA
• OSTI ID: 5768491
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 26:10; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ACETYLCHOLINE
ALCOHOLS
ALKALI METAL COMPOUNDS
ALKALI METAL ISOTOPES
AMINES
AMMONIUM COMPOUNDS
ANIMALS
AQUATIC ORGANISMS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CELL MEMBRANES
CHLORIDES
CHLORINE COMPOUNDS
CHOLINE
DAYS LIVING RADIOISOTOPES
DOSE-RESPONSE RELATIONSHIPS
DRUGS
ELECTRON SPIN RESONANCE
ESTERS
FISHES
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
INTERMEDIATE MASS NUCLEI
ISOMERIC TRANSITION ISOTOPES
ISOTOPES
KINETICS
LABELLED COMPOUNDS
LIPOTROPIC FACTORS
MAGNETIC RESONANCE
MEMBRANE PROTEINS
MEMBRANE TRANSPORT
MEMBRANES
MINUTES LIVING RADIOISOTOPES
NEUROREGULATORS
NICOTINIC ACID
NUCLEI
ODD-ODD NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PARASYMPATHOMIMETICS
PROTEINS
PYRIDINES
QUATERNARY COMPOUNDS
RADIOISOTOPES
REACTION KINETICS
RECEPTORS
RESONANCE
RUBIDIUM 86
RUBIDIUM CHLORIDES
RUBIDIUM COMPOUNDS
RUBIDIUM ISOTOPES
TRITIUM COMPOUNDS
VERTEBRATES
VITAMIN B GROUP
VITAMINS