Linked Life Data

16289123

Source:http://linkedlifedata.com/resource/pubmed/id/16289123

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
2005-12-7
pubmed:abstractText
Anticholinesterases (antiChEs) are increasingly used for treating patients with neurodegenerative diseases, but the dependence of their effects on the integrity of cholinergic functions has not yet been analyzed at the molecular level. Here, we report that manipulation of muscarinic neurotransmission confers drastic changes on antiChE responses in the rat brain. In the brains of naïve, un-stressed rats, the irreversible organophosphate antiChE, diisopropylfluorophosphonate (DFP) induced post-treatment accumulation of catalytically active G1 monomers of acetylcholinesterase (AChE). Pre-treatment with the selective M1 muscarinic antagonist, pirenzepine, but not the general muscarinic antagonist, scopolamine, attenuated this G1 increase. DFP-enhanced AChE gene expression was accompanied by diverted splicing from the primary AChE-S mRNA variant, encoding G4 synaptic membrane AChE-S tetramers, to "readthrough" AChE-R mRNA, which encodes soluble G1 monomers. Both the mRNA increase and the shifted splicing were long lasting (>24 h) and common to the parietal cortex and hippocampal CA1 and CA3 neurons. Importantly, the splicing shift was maximal under DFP alone, as compared with sham-injected rats, and virtually preventable by pre-treatment with pirenzepine. In contrast, induction of AChE transcription was less dependent on muscarinic function, resulting in AChE-S but not AChE-R increases. Our findings demonstrate distinct regulation of the enhanced transcription and the alternative splicing reactions to antiChE treatment and shed new light on the differential responses to antiChEs of demented patients with increasingly impaired cholinergic neurotransmission.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0009-2797
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
157-158
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
105-13
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Muscarinic modulations of neuronal anticholinesterase responses.
pubmed:affiliation
Department of Biological Chemistry and The Eric Roland Center for Neurodegenerative Diseases, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't