Mutations in presenilin-1 (PS1), the leading cause of early-onset, autosoma
l-dominant familial Alzheimer's disease (FAD), enhance calcium signaling me
diated by inositol 1,4,5-trisphosphate (IP3). To elucidate the subcellular
mechanisms underlying this enhancement, we used high resolution line-scanni
ng confocal microscopy to image elementary calcium release events ("puffs")
in Xenopus oocytes expressing wild-type or mutant PS1. Here we report that
mutant pal-rendered puffs more sensitive to IP3 and increased both the mag
nitude and the rate of calcium release during each event. These effects wer
e not attributable to quantitative changes in the levels of IP3 receptors o
r their distribution on the ER, but were instead associated with an abnorma
l elevation of ER calcium stores. Together, our results suggest that the ef
fects of mutant pal on calcium signaling are manifested predominantly at th
e level of the regulation of calcium stores rather than via perturbations i
n the numbers or activity of IP3-activated calcium release channels. (C) 20
01 Academic Press.