Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors
Four nerve agents and one therapeutic organophosphate (OP) anticholinesterase (anti-ChE) bind to acetylcholine (ACh) receptors, inhibit or modulate binding of radioactive ligands to these receptors, and modify events regulated by them. The affinity of nicotinic (n) ACh receptors of Torpedo electric organs and most muscarinic (m) ACh receptors of rat brain and N1E-115 neuroblastoma cultures for the OP compounds was usually two to three orders of magnitude lower than concentrations required to inhibit 50% (IC-50) of ACh-esterase activity. However, a small population of m-ACh receptors had an affinity as high as that of ACh-esterase for the OP compound. This population is identified by its high-affinity (3H)-cis-methyldioxolane ((3H)-CD) binding. Although sarin, soman, and tabun had no effect, (O-ethyl S(2-(diisopropylamino)ethyl)) methyl phosphonothionate (VX) and echothiophate inhibited competitively the binding of (3H)-quinuclidinyl benzilate ((3H)-QNB) and (3H)-pirenzepine ((3H)-PZ) to m-ACh receptors. However, VX was more potent than echothiophate in inhibiting this binding and 50-fold more potent in inhibiting carbamylcholine (carb)-stimulated (3H)-cGMP synthesis in N1E-115 neuroblastoma cells--both acting as m receptor antagonist. All five OPs inhibited (3H)-CD binding, with IC-50s of 3, 10, 40, 100, and 800 nM for VX, soman, sarin, echothiophate, and tabun, respectively. The OP anticholinesterases also bound to allosteric sites on the n-ACh receptor (identified by inhibition of (3H)-phencyclidine binding), but some bound as well to the receptor's recognition site (identified by inhibition of (125I)-alpha-bungarotoxin binding). Soman and echothiophate in micromolar concentrations acted as partial agonists of the n-ACh receptor and induced receptor desensitization. On the other hand, VX acted as an open channel blocker of the activated receptor and also enhanced receptor desensitization.
- Research Organization:
- Univ. of Maryland, Baltimore (USA)
- OSTI ID:
- 6101575
- Journal Information:
- J. Biochem. Toxicol.; (United States), Vol. 3
- Country of Publication:
- United States
- Language:
- English
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ACETYLCHOLINE
RECEPTORS
CHOLINESTERASE
BIOCHEMICAL REACTION KINETICS
ENZYME INHIBITORS
AFFINITY
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FISHES
IODINE 125
LIGANDS
ORGANIC PHOSPHORUS COMPOUNDS
RATS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
TUMOR CELLS
AMINES
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ANIMAL CELLS
ANIMALS
AQUATIC ORGANISMS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
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CENTRAL NERVOUS SYSTEM
DAYS LIVING RADIOISOTOPES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
ENZYMES
ESTERASES
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HYDROLASES
INTERMEDIATE MASS NUCLEI
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
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PARASYMPATHOMIMETICS
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QUATERNARY COMPOUNDS
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550201* - Biochemistry- Tracer Techniques