Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase

Weihua Xie, Judith A. Stribley, Arnaud Chatonnet, Phillip J. Wilder, A Angie Rizzino, Rodney D McComb, Palmer Taylor, Steven Heye Hinrichs, Oksana Lockridge

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

Acetylcholinesterase (ACHE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses and is believed to play an important role in neural development. Targeted deletion of four exons of the ACHE gene reduced AChE activity by half in heterozygous mutant mice and totally eliminated AChE activity in nullizygous animals. Butyrylcholinesterase (EC 3.1.1.8) activity was normal in AChE -/- mice. Although nullizygous mice were born alive and lived up to 21 days, physical development was delayed. The neuromuscular junction of 12-day-old nullizygous animals appeared normal in structure. Nullizygous mice were highly sensitive to the toxic effects of the organophosphate diisopropylfluorophosphate and to the butyrylcholinesterase-specific inhibitor bambuterol. These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE and that the inhibition of targets other than AChE by organophosphorus agents results in death.

Original languageEnglish (US)
Pages (from-to)896-902
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume293
Issue number3
StatePublished - Jun 1 2000

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Organophosphates
Acetylcholinesterase
Butyrylcholinesterase
Genes
Isoflurophate
Neuromuscular Junction
Poisons
Cholinesterases
Synapses
Cholinergic Agents
Action Potentials
Exons
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. / Xie, Weihua; Stribley, Judith A.; Chatonnet, Arnaud; Wilder, Phillip J.; Rizzino, A Angie; McComb, Rodney D; Taylor, Palmer; Hinrichs, Steven Heye; Lockridge, Oksana.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 293, No. 3, 01.06.2000, p. 896-902.

Research output: Contribution to journalArticle

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