{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T16:45:00Z","timestamp":1758991500383},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2006,6,8]],"date-time":"2006-06-08T00:00:00Z","timestamp":1149724800000},"content-version":"vor","delay-in-days":5120,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Biochem. Toxicol."],"published-print":{"date-parts":[[1992,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The effects of the organophosphorus anticholinesterase paraoxon on the binding of radioactive ligands to the M<jats:sub>3<\/jats:sub> subtype of the muscarinic receptor and receptor\u2010coupled synthesis of second messengers in intact rat submaxillary gland (SMG) cells were investigated. The binding of [<jats:sup>3<\/jats:sup>H]quinuclidinyl benzilate ([<jats:sup>3<\/jats:sup>H]QNB) was most sensitive to atropine and the M<jats:sub>3<\/jats:sub>\u2010specific antagonist 4\u2010DAMP followed by pirenzepine and least sensitive to the cardioselective M<jats:sub>2<\/jats:sub> antagonist AFDX116. This, and the binding characteristics of [<jats:sup>3<\/jats:sup>H]4\u2010DAMP, confirmed that the muscarinic receptors in this preparation are of the M<jats:sub>3<\/jats:sub> subtype. Activation of these muscarinic receptors by carbamylcholine (CBC) produced both stimulation of phosphoinositide (PI) hydrolysis and inhibition of cAMP synthesis, suggesting that this receptor subtype couples to both effector systems.<\/jats:p><jats:p>Paraoxon (100 \u03bcM) reduced B<jats:sub>max<\/jats:sub> of [<jats:sup>3<\/jats:sup>H]4\u2010DAMP binding from 27 \u00b1 4 to 13 \u00b1 3 fmol\/mg protein with nonsignificant change in affinity, suggesting noncompetitive inhibition of binding by paraoxon. Like the agonist CBC, paraoxon inhibited the forskolininduced cAMP formation in SMG cells with an EC<jats:sub>50<\/jats:sub> of 200 nM, but paraoxon was &gt; 500 fold more potent than CBC. However, while the inhibition by CBC was counteracted by 2 \u03bcM atropine, that by paraoxon was unaffected by up to 100 \u03bcM atropine. It suggested that this effect of paraoxon was not via binding to the muscarinic receptor. Paraoxon did not affect \u03b2\u2010adrenoreceptor function in the preparation, since it did not affect the 10 \u03bcM isoproterenol\u2010induced cAMP synthesis, which was inhibited totally by 10 \u03bcM propranolol and partially by CBC. Paraoxon had a small but significant effect on CBC\u2010stimulated PI metabolism in the SMG cells. It is suggested that paraoxon binds to two different sites in these SMG cells. One is an allosteric site on the M<jats:sub>3<\/jats:sub> muscarinic receptor which affects ligand binding and may modulate receptor function. The other site may be on the G<jats:sub>i<\/jats:sub> proteinadenylyl cyclase system, and produces CBC\u2010like action, that is, inhibition of the forskolin\u2010stimulated [<jats:sup>3<\/jats:sup>H]cAMP synthesis, and is unaffected by atropine inhibition of the muscarinic receptor. This adds to the complexity of paraoxon actions on muscarinic receptors and their effector systems.<\/jats:p>","DOI":"10.1002\/jbt.2570070210","type":"journal-article","created":{"date-parts":[[2006,10,18]],"date-time":"2006-10-18T01:47:29Z","timestamp":1161136049000},"page":"125-132","source":"Crossref","is-referenced-by-count":24,"title":["Differential effects of paraoxon on the M<sub>3<\/sub> muscarinic receptor and its effector system in rat submaxillary gland cells"],"prefix":"10.1002","volume":"7","author":[{"given":"Elsayed A. 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