Organophosphate-induced alterations in muscarinic receptor binding and phosphoinositide hydrolysis in the human SK-N-SH cell line.
Low level, chronic exposure (0.1 nM, 24 hrs) to the organophosphate paraoxon significantly inhibits N-[3H]methylscopolamine ([3H]NMS) binding to muscarinic receptors in a noncompetitive manner in the SK-N-SH neuroblastoma cell line. The effect of paraoxon on muscarinic receptor-mediated phosphoinositide hydrolysis was also investigated. At 0.1 nM, paraoxon caused a time-dependent increase in the accumulation of inositol phosphates, while the classical muscarinic receptor agonist carbachol was virtually ineffective at low concentrations. In contrast, carbachol-induced increases in phosphoinositide hydrolysis at higher concentrations (1 mM) were markedly larger (five-fold) than the increases induced by PX. Approximately 50% of the maximal increase in the accumulation of inositol phosphates due to paraoxon treatment was antagonized by saturating concentrations of muscarinic receptor antagonists, while the response to carbachol was completely antagonized. In addition, chronic treatment (24 hrs) of SK-N-SH cells with pertussis toxin blocked 75% of the stimulatory effects of carbachol, but inhibited only 38% of the paraoxon-induced response. Neomycin, a phospholipase C inhibitor, completely blocked both the paraoxon and carbachol-induced stimulation of phosphoinositide hydrolysis. The results suggest that paraoxon can modulate signal transduction by indirect activation of muscarinic receptors as well as by acting at a distal site along the pathway.
Katz
L S
LS
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts.
Marquis
J K
JK
D000110:Acetylcholinesterase / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D009355:Neomycin / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010261:Paraoxon / Q000494:pharmacology; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007295:Inositol Phosphates; D009943:Organophosphorus Compounds; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D002217:Carbachol; D037342:Pertussis Toxin; D000110:Acetylcholinesterase; D010738:Type C Phospholipases; D009355:Neomycin; D010261:Paraoxon