Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the acute effects of organophosphorus esters are generally ascribed to inhibition of acetylcholinesterase, work in this laboratory and others indicates that organophosphorus insecticides also interact directly with cholinergic receptors. The current study verifies that the insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothionate (chlorpyrifos) and its oxon metabolite inhibits acetylcholinesterase (AChE). The metabolite inhibits rat brain AChE three orders of magnitude more rapidly than chlorpyrifos. In addition to their ability to inhibit AChE, these compounds were shown to interact directly with muscarinic receptors of rat striatum. The oxon metabolite bound at low concentrations to muscarinic receptors labeled by the muscarinic agonist [3H] cis-methyldioxolane; chlorpyrifos oxon bound with an IC50 value of 22.1 +/- 3.6 nM. The receptors bound by chlorpyrifos oxon account for approximately 30% of muscarinic receptors of the striatum and are of the m2 subtype. The binding of chlorpyrifos oxon to the m2 receptor results in a covalent modification of the receptor that does not interfere with the ability of the receptor to interact with the agonist carbachol. This receptor modification may be responsible for the inhibition of adenylate cyclase activity by chlorpyrifos oxon. The oxon inhibited adenylate cyclase with an IC50 of 155 +/- 78 nM. The inhibition of adenylate cyclase activity was not blocked by atropine and was additive to that produced by carbachol. The altering of postreceptor signal transduction by chlorpyrifos oxon may interfere with normal cellular signaling, thereby disturbing neurological function. Direct interaction of chlorpyrifos oxon with muscarinic receptors and associated signal transduction is a potential mechanism of neurotoxicity that is independent of AChE inhibition.
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PMID:Chlorpyrifos oxon binds directly to muscarinic receptors and inhibits cAMP accumulation in rat striatum. 751 60

Although the neurotoxicity of organophosphorus compounds is generally attributed to inhibition of acetylcholinesterase, recent reports have indicated that direct interactions with muscarinic receptors and signal transduction may be an additional mechanism of neurotoxicity. We have previously shown that the organophosphorus insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate (chlorpyrifos) binds directly to muscarinic receptors and inhibits adenylate cyclase of rat striatum. We have further pursued those results in this study by investigating the effect of chlorpyrifos oxon in NG108-15 neuroblastoma-glioma cells and Chinese hamster ovary cells transfected with cDNA for human m2 or m4 muscarinic receptor subtypes. At millimolar concentrations, chlorpyrifos oxon inhibited [3H]QNB binding in all cell lines. Likewise, [3H]CD binding was inhibited in NG108-15 and CHO-Hm2 cells. When the effect of chlorpyrifos oxon on adenylate cyclase was examined, the oxon was found to inhibit adenylate cyclase at millimolar concentrations. Though this effect on cyclase required greater concentrations of oxon than the comparable effect in striatal cells, it displayed the common characteristic of being atropine-insensitive, suggesting that the effect on cyclase was not muscarinic receptor dependent. The inhibition of adenylate cyclase produced by chlorpyrifos oxon was not eliminated in pertussis toxin treated cells, lending further support to the idea that it is not a receptor-mediated event, and suggesting a potential direct interaction of chlorpyrifos oxon with the adenylate cyclase molecule.
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PMID:In vitro effect of chlorpyrifos oxon on muscarinic receptors and adenylate cyclase. 756 87