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Titre du document / Document title

The presenilin 1 ΔE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations

Auteur(s) / Author(s)


Résumé / Abstract

We studied effects of the familial Alzheimer's disease presenilin 1 (PS1) exon 9 deletion (PS1-ΔE9) mutation on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular Ca2+ concentrations ([Ca2+]i) in human SH-SY5Y neuroblastoma cells. We demonstrate that PS1-ΔE9 cells have an enhanced basal PI hydrolysis and [Ca2+]ias compared with both wild type PS1 (PS1-WT) and nontransfected (NT) cells. Both were reversed by the phospholipase C (PLC) inhibitor neomycin. The PS1-ΔE9-related high basal [Ca2+]i was also reversed by xestospongin C confirming that this effect was inositol trisphosphate receptor-mediated. Carbachol gave a greater stimulation of [Ca2+]i in PS1-AE9 cells that took longer to return to basal as compared with responses seen in NT and PS1-WT cells. This long tail-off effect seen in PS1-ΔE9 cells after carbachol stimulation was reversed by xestospongin C and dantrolene, suggesting that it was mediated by inositol trisphosphate receptor and ryanodine receptor amplification of Ca2+. Ruthenium red only reduced carbachol peak elevations of [Ca2+]i in NT and PS1-WT cells and not in PS1-ΔE9 cells. No significant between cell type differences were seen for basal and carbachol-stimulated [Ca2+]i with either ryanodine or the endoplasmic reticulum Ca2+ATPase inhibitor cyclopiazonic acid. Immunostaining experiments revealed that for all the cell types PS1 is present at the plasma membrane and colocalizes with N-cadherin, a component of the cell-cell adhesion complex. Immunoblotting of cell extracts for PLC-β1 showed that, compared with NT and PS1-WT cells, the PS1-ΔE9 transfectants gave a relative increase in levels of the calpain generated N-terminal fragment (100 kDa) over full-length (150 kDa) PLC-β1. Our results suggest that the PS1-ΔE9 mutation causes upstream changes in PI signaling with enhanced basal PLC activity as a primary effect that leads to a higher [Ca2+]i. This may provide a novel mechanism by which the PS1-ΔE9 mutation sensitizes cells to apoptotic stimuli and enhanced amyloid β generation.

Revue / Journal Title

The Journal of biological chemistry    ISSN  0021-9258   CODEN JBCHA3 

Source / Source

2002, vol. 277, no39, pp. 36646-36655 [10 page(s) (article)]

Langue / Language


Editeur / Publisher

American Society for Biochemistry and Molecular Biology, Bethesda, MD, ETATS-UNIS  (1905) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 3082, 35400010932177.1100

Nº notice refdoc (ud4) : 13938730

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