Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

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Abstract
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 competitivel the binding of 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]‐α‐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. It is suggested that the toxicity of OP anticholinesterases may include their action on n‐ACh as well as m‐ACh receptors if their concentrations in circulation rise above micromolar levels. At nanomolar concentrations their toxicity is due mainly to their inhibition of ACh‐esterase. However, at these low concentrations, many OP anticholinesterases (eg, VX and soman) may affect a small population of m‐ACh receptors, which have a high affinity for CD. Such effects on m‐ACh receptors may play an important role in the toxicity of certain OP compounds.