Differential effects of paraoxon on the M3 muscarinic receptor and its effector system in rat submaxillary gland cells
✍ Scribed by Abdallah, Elsayed A. M. ;Jett, David A. ;Eldefrawi, Mohyee E. ;Eldefrawi, Amira T.
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 784 KB
- Volume
- 7
- Category
- Article
- ISSN
- 0887-2082
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✦ Synopsis
The effects of the organophosphorus anticholinesterase paraoxon on the binding of radioactive ligands to the M, subtype of the muscarinic receptor and receptor-coupled synthesis of second messengers in intact rat submaxillary gland (SMG) cells were investigated. The binding of 13Hlquinuclidinyl benzilate (I3H1QNB) was most sensitive to atropine and the M,-specific antagonist 4-DAMP followed by pirenzepine and least sensitive to the cardioselective M2 antagonist AFDX116. This, and the binding characteristics of 13H]4-DAMP, confirmed that the muscarinic receptors in this preparation are of the M3 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.
Paraoxon (100 pM) reduced B, , , of 13H14-DAMP binding from 27 2 4 to 13 f 3 fmollmg protein with nonsignificant change in affinity, suggesting noncompetitive inhibition of binding by paraoxon. Like the agonist CBC, paraoxon inhibited the forskolininduced cAMPformation in SMG cells with an EC,, of 200 nM, but paraoxon was > 500 fold more potent than CBC. However, while the inhibition by CBC was counteracted by 2 pM atropine, that by paraoxon was unaffected by up to 100 pM atropine. It suggested that this effect of paraoxon was not via binding to the muscarinic receptor. Paraoxon did not affect padrenoreceptor function in the preparation, since it did not affect the 10 pM isoproterenol-induced cAMP synthesis, which was inhibited totally by 10 pM propranolol and partially by CBC. Paraoxon had a small but significant effect on CBC-stimulated PI metabolism in the SMG cells. It is suggested that paraoxon