Perturbations in intracellular Ca2+ signaling may represent one mechanism u
nderlying Alzheimer's disease (AD). The presenilin-1 gene (PS1), associated
with the majority of early onset familial AD cases, has been implicated in
this signaling pathway. Here we used the Xenopus oocyte expression system
to investigate in greater detail the role of PS1 in intracellular Ca2+ sign
aling pathways. Treatment of cells expressing wild-type PSI with a cell sur
face receptor agonist to stimulate the phosphoinositide second messenger pa
thway evoked Ca2+-activated Cl- currents that were significantly potentiate
d relative to controls. To determine which elements of the signal transduct
ion pathway are responsible for the potentiation, we used photolysis of cag
ed inositol 1,4,5-trisphosphate (IP3) and fluorescent Ca2+ imaging to demon
strate that PSI potentiates IP3-mediated release of Ca2+ from internal stor
es. We show that an AD-linked mutation produces a potentiation in Ca2+ sign
aling that is significantly greater than that observed for wild-type PSI an
d that cannot be attributed to differences in protein expression levels. Ou
r findings support a role for PS1 in modulating IP,-mediated Ca2+ liberatio
n and suggest that one pathophysiological mechanism by which PS1 mutations
contribute to AD neurodegeneration may involve perturbations of this functi
on.