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Alzheimer's Presenilin‐1 Mutation Potentiates Inositol 1,4,5‐Trisphosphate‐Mediated Calcium Signaling in Xenopus
Author(s) -
Leissring Malcolm A.,
Paul Brooke A.,
Parker Ian,
Cotman Carl W.,
LaFerla Frank M.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1999.721061.x
Subject(s) - presenilin , inositol , xenopus , calcium signaling , neuroscience , calcium , mutation , biology , microbiology and biotechnology , signal transduction , chemistry , alzheimer's disease , genetics , medicine , receptor , gene , disease
: Perturbations in intracellular Ca 2+ signalingmay represent one mechanism underlying Alzheimer's disease (AD). Thepresenilin‐1 gene ( PS1 ), associated with the majority of early onsetfamilial AD cases, has been implicated in this signaling pathway. Here we usedthe Xenopus oocyte expression system to investigate in greater detailthe role of PS1 in intracellular Ca 2+ signaling pathways. Treatmentof cells expressing wild‐type PS1 with a cell surface receptor agonist tostimulate the phosphoinositide second messenger pathway evoked Ca 2+ ‐activated Cl ‐ currents that were significantly potentiatedrelative to controls. To determine which elements of the signal transductionpathway are responsible for the potentiation, we used photolysis of cagedinositol 1,4,5‐triphosphate (IP 3 ) and fluorescent Ca 2+ imaging to demonstrate that PS1 potentiates IP 3 ‐mediated release ofCa 2+ from internal stores. We show that an AD‐linked mutationproduces a potentiation in Ca 2+ signaling that is significantlygreater than that observed for wild‐type PS1 and that cannot be attributed todifferences in protein expression levels. Our findings support a role for PS1in modulating IP 3 ‐mediated Ca 2+ liberation and suggestthat one pathophysiological mechanism by which PS1 mutations contribute to AD neurodegeneration may involve perturbations of this function.