Article
Organophosphorus compounds preferentially affect second messenger systems coupled to M2/M4 receptors in rat frontal cortex

https://doi.org/10.1016/0361-9230(95)02044-6Get rights and content

Abstract

Recent reports indicate that organophosphate insecticides, in addition to inhibiting acetylcholinesterase activity, can bind directly at a subset of muscarinic receptors, which also bind cis-methyldioxolane with high affinity. Muscarinic receptors are known to act through at least two second messenger systems, either the stimulation of phosphoinositide turnover (mediated through the M1 and M3 receptor subtypes) or the inhibition of cAMP formation (mediated through the M2 and M4 receptor subtypes). We have investigated the action of the active forms of parathion, malathion, and chlorpyrifos (paraoxon, malaoxon, and chlorpyrifos oxon, respectively) on these second messenger systems in cortical slices from adult male Long-Evans rats. Paraoxon, malaoxon, and chlorpyrifos oxon (10−8 to 10−4 M) inhibited forskolin-stimulated cAMP formation in a concentration-dependent manner. The effect on cAMP formation was blocked by the muscarinic antagonist atropine (10 μM). These results suggest that paraoxon, malaoxon, and chlorpyrifos oxon can act as agonists at the M2 and/or M4 subset of muscarinic receptors. In addition, chlorpyrifos may have another site of action. In contrast, none of the organophosphates had any effect on basal or carbachol-stimulated phosphoinositide hydrolysis. The differential activity on these two second messenger systems make it unlikely that the observed effects on cAMP formation are due to increases in endogenous acetylcholine resulting from inhibition of acetylcholinesterase.

References (39)

  • T.J. Shafer et al.

    Mechanisms underlying AlCl3 inhibition of agonist stimulated inositol phosphate accumulation. Role of calcium, G-proteins, phospholipase C and protein kinase C

    Biochem. Pharmacol.

    (1994)
  • L.S. Volpe et al.

    In vitro modulation of bovine caudate muscarinic receptor number by organophosphates and carbamates

    Toxicol. Appl. Pharmacol.

    (1985)
  • T.R. Ward et al.

    Correlation of the anticholinesterase activity of a series of organophosphates with their ability to compete with agonist binding to muscarinic receptors

    Toxicol. Appl. Pharmacol.

    (1993)
  • E.A.M. Abdallah et al.

    Differential effects of paraoxon on the M3 muscarinic receptor and its effector system in rat submaxillary gland cells

    J. Biochem. Toxicol.

    (1992)
  • C. Allgaier et al.

    Muscarine receptors regulating electrically evoked release of acetylcholine in hippocampus are linked to pertussis toxin-sensitive G proteins but not to adenylate cyclase

    J. Neurochem.

    (1993)
  • A. Ashkenazi et al.

    An M2 muscarinic receptor subtype coupled to both adenyl cyclase and phosphoinositide turnover

    Science

    (1987)
  • N.M.S. Bakry et al.

    Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

    J. Biochem. Toxicol.

    (1988)
  • M.J. Berridge et al.

    Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands

    Biochem. J.

    (1988)
  • E. Brown et al.

    Inositol phospholipid hydrolysis in rat cerebral cortical slices. I. Receptor characterization

    J. Neurochem.

    (1984)
  • Cited by (99)

    • Cell signaling mechanisms in developmental neurotoxicity

      2022, Reproductive and Developmental Toxicology
    • Cell signaling mechanisms in developmental neurotoxicity

      2017, Reproductive and Developmental Toxicology
    View all citing articles on Scopus
    View full text