Document Detail

The presenilin 1 deltaE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations.
MedLine Citation:
PMID:  12121968     Owner:  NLM     Status:  MEDLINE    
We studied effects of the familial Alzheimer's disease presenilin 1 (PS1) exon 9 deletion (PS1-DeltaE9) mutation on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular Ca(2+) concentrations ([Ca(2+)](i)) in human SH-SY5Y neuroblastoma cells. We demonstrate that PS1-DeltaE9 cells have an enhanced basal PI hydrolysis and [Ca(2+)](i) as compared with both wild type PS1 (PS1-WT) and nontransfected (NT) cells. Both were reversed by the phospholipase C (PLC) inhibitor neomycin. The PS1-DeltaE9-related high basal [Ca(2+)](i) was also reversed by xestospongin C confirming that this effect was inositol trisphosphate receptor-mediated. Carbachol gave a greater stimulation of [Ca(2+)](i) in PS1-DeltaE9 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-DeltaE9 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 Ca(2+). Ruthenium red only reduced carbachol peak elevations of [Ca(2+)](i) in NT and PS1-WT cells and not in PS1-DeltaE9 cells. No significant between cell type differences were seen for basal and carbachol-stimulated [Ca(2+)](i) with either ryanodine or the endoplasmic reticulum Ca(2+) ATPase inhibitor cyclopiazonic acid. Immunostaining experiments revealed that for all the cell types PS1 is present at the plasma membrane and co-localizes with N-cadherin, a component of the cell-cell adhesion complex. Immunoblotting of cell extracts for PLC-beta1 showed that, compared with NT and PS1-WT cells, the PS1-DeltaE9 transfectants gave a relative increase in levels of the calpain generated N-terminal fragment (100 kDa) over full-length (150 kDa) PLC-beta1. Our results suggest that the PS1-DeltaE9 mutation causes upstream changes in PI signaling with enhanced basal PLC activity as a primary effect that leads to a higher [Ca(2+)](i). This may provide a novel mechanism by which the PS1-DeltaE9 mutation sensitizes cells to apoptotic stimuli and enhanced amyloid beta generation.
Angel Cedazo-Minguez; Bogdan O Popescu; Maria Ankarcrona; Takeshi Nishimura; Richard F Cowburn
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-07-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-23     Completed Date:  2002-11-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  36646-55     Citation Subset:  IM    
Section of Experimental Geriatrics, Karolinska Institutet, Neurotec, Kliniskt Forskningscentrum (KFC), 141 86 Huddinge, Sweden.
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MeSH Terms
Amyloid beta-Protein / metabolism
Cadherins / metabolism
Calcium / metabolism*
Carbachol / metabolism
Cell Line
Cell Membrane / metabolism
Coloring Agents / pharmacology
Dantrolene / pharmacology
Endoplasmic Reticulum / metabolism
Enzyme Inhibitors / pharmacology
Indoles / pharmacology
Macrocyclic Compounds
Membrane Proteins / genetics*,  metabolism*
Microscopy, Confocal
Muscle Relaxants, Central / pharmacology
Neomycin / pharmacology
Oxazoles / pharmacology
Protein Binding
Protein Structure, Tertiary
Ruthenium Red / pharmacology
Ryanodine / pharmacology
Time Factors
Tumor Cells, Cultured
Type C Phospholipases / antagonists & inhibitors,  metabolism*
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Cadherins; 0/Coloring Agents; 0/Enzyme Inhibitors; 0/Indoles; 0/Macrocyclic Compounds; 0/Membrane Proteins; 0/Muscle Relaxants, Central; 0/Oxazoles; 0/PSEN1 protein, human; 0/Presenilin-1; 0/xestospongin A; 11103-72-3/Ruthenium Red; 1404-04-2/Neomycin; 15662-33-6/Ryanodine; 18172-33-3/cyclopiazonic acid; 51-83-2/Carbachol; 7261-97-4/Dantrolene; 7440-70-2/Calcium; EC 3.1.4.-/Type C Phospholipases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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