Presenilin-2 Mutations Modulate Amplitude and Kinetics of Inositol 1,4,5-Trisphosphate-mediated Calcium Signals

Mutations in the two presenilin genes (PS1, PS2) account for the majority of early-onset familial Alzheimer's disease (FAD) cases. Converging evidence from a variety of experimental systems, including fibroblasts from FAD patients and transgenic animals, indicates thatPS1 mutations modulate int...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-11, Vol.274 (46), p.32535-32538
Main Authors: Leissring, Malcolm A., Parker, Ian, LaFerla, Frank M.
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Animals
Calcium Channels - metabolism
Calcium Signaling - genetics
Gene Expression
Humans
Inositol 1,4,5-Trisphosphate - analogs & derivatives
Inositol 1,4,5-Trisphosphate - metabolism
Inositol 1,4,5-Trisphosphate Receptors
Kinetics
Membrane Proteins - genetics
Microinjections
Mutation
Oocytes
Photolysis
Presenilin-2
PS2 gene
Receptors, Cytoplasmic and Nuclear - metabolism
RNA, Complementary
Ultraviolet Rays
Xenopus
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Summary:Mutations in the two presenilin genes (PS1, PS2) account for the majority of early-onset familial Alzheimer's disease (FAD) cases. Converging evidence from a variety of experimental systems, including fibroblasts from FAD patients and transgenic animals, indicates thatPS1 mutations modulate intracellular calcium signaling pathways. Despite the potential relevance of these changes to the pathogenesis of FAD, a comparable effect for PS2 has not yet been demonstrated experimentally. We examined the effects of wild-type PS2, and both of the identified FAD mutations inPS2, on intracellular calcium signaling inXenopus oocytes. Inositol 1,4,5-trisphosphate (IP3)-evoked calcium signals were significantly potentiated in cells expressing either of the PS2 mutations relative to wild-type PS2-expressing cells and controls. Decay rates of calcium signals were also significantly accelerated in mutantPS2-expressing cells in a manner dependent upon IP3 concentration. The finding that mutations in bothPS1 and PS2 modulate intracellular calcium signaling suggests that these disturbances may represent a common pathogenic mechanism of presenilin-associated FAD.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.46.32535