In Vivo Characterization of Intracellular Signaling Pathways Activated by the Nerve Agent Sarin
Abstract
Organophosphorous (OP) nerve agents, such as sarin, exert acute effects by inhibiting acetylcholinesterase in the central and peripheral nervous systems, which results in accumulation of acetylcholine and, in turn, an excessive stimulation of nicotinic and muscarinic receptors. Preliminary evidence using diverse OPs indicates that the DARPP-32/PP-1 signaling pathway is activated by nicotinic receptor stimulation. We investigated whether treatment of whole animals with sarin activated the DARPP-32/PP-1 signaling cascade. Both a seizure-inducing dose (1.0 x LD50) and a sub-seizure threshold dose (0.5 x LD50) of sarin were tested. Rats receiving the sub-threshold dose were asymptomatic for seizures. A selective increase in phospho-T75 DARPP-32 levels was observed in striatum from these rats 30 min after exposure. Rats displaying seizure activity following administration of a 1.0 x LD50 dose of sarin displayed changes in several phosphoproteins, including T75 DARPP-32. Transient increases in T75 DARPP-32, T183 ERK, and S133 CREB phosphorylation were followed by reductions in phosphorylation at three DARPP-32 sites (T34, S102, and S137) and reductions in 594 spinophilin and S897 NR1. Another glutamate receptor site, S845 GluR1, was unaffected by sarin treatment. This study represents the first comprehensive analysis of signal transduction pathways activated in response to sarin exposure in whole animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2004
- Accession Number
- ADA442898
Entities
People
- Allen A. Fienberg
- Gretchen L. Snyder
- John H. McDonough
- Joseph P. Hendrick
- Tsung-ming A. Shih
Organizations
- United States Army Medical Research Institute of Chemical Defense