Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid β(1-42)
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
23206502
DOI
10.1016/j.neuropharm.2012.11.014
PII: S0028-3908(12)00561-8
Knihovny.cz E-zdroje
- MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- křečci praví MeSH
- kultivované buňky MeSH
- lidé MeSH
- myši transgenní MeSH
- myši MeSH
- peptidové fragmenty antagonisté a inhibitory metabolismus MeSH
- receptor muskarinový M1 metabolismus MeSH
- receptory spřažené s G-proteiny antagonisté a inhibitory metabolismus MeSH
- rozpřahující látky farmakologie MeSH
- vazba proteinů účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amyloid beta-protein (1-42) MeSH Prohlížeč
- amyloidní beta-protein MeSH
- peptidové fragmenty MeSH
- receptor muskarinový M1 MeSH
- receptory spřažené s G-proteiny MeSH
- rozpřahující látky MeSH
The overproduction of β-amyloid (Aβ) fragments in transgenic APPswe/PS1dE9 mice results in formation of amyloid deposits in the cerebral cortex and hippocampus starting around four months of age and leading to cognitive impairment much later. We have previously found an age and transgene-dependent weakening of muscarinic receptor-mediated transmission that was not present in young (6-10-week-old) animals but preceded both amyloid deposits and cognitive deficits. Now we investigated immediate and prolonged in vitro effects of non-aggregated Aβ(1-42) on coupling of individual muscarinic receptor subtypes expressed in CHO (Chinese hamster ovary) cells and their underlying mechanisms. Immediate application of 1 μM Aβ(1-42) had no effect on the binding of the muscarinic antagonist N-methylscopolamine or the agonist carbachol. In contrast, 4-day treatment of CHO cells expressing the M1 muscarinic receptor with 100 nM Aβ(1-42) significantly changed the binding characteristics of the muscarinic agonist carbachol and reduced the extent of the M1 receptor-stimulated breakdown of phosphatidylinositol while it did not demonstrate overt toxic effects. The treatment had no influence on the expression of either G-proteins or muscarinic receptors. In concert, we found no change in the gene expression of muscarinic receptor subtypes and gene or protein expression of the G(s), G(q/11), and G(i/o) G-proteins in the cerebral cortex of young adult APPswe/PS1dE9 mice that demonstrate high concentrations of soluble Aβ(1-42) and impaired muscarinic receptor-mediated G-protein activation. Our results provide strong evidence that the initial injurious effects of Aβ(1-42) on M1 muscarinic receptor-mediated transmissionis is due to compromised coupling of the receptor with G(q/11) G-protein.
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