Subcellular mechanisms of presenilin-mediated enhancement of calcium signaling.
Mutations in presenilin-1 (PS1), the leading cause of early-onset, autosomal-dominant familial Alzheimer's disease (FAD), enhance calcium signaling mediated by inositol 1,4,5-trisphosphate (IP3). To elucidate the subcellular mechanisms underlying this enhancement, we used high resolution line-scanning confocal microscopy to image elementary calcium release events ("puffs") in Xenopus oocytes expressing wild-type or mutant PS1. Here we report that mutant PS1-rendered puffs more sensitive to IP3 and increased both the magnitude and the rate of calcium release during each event. These effects were not attributable to quantitative changes in the levels of IP3 receptors or their distribution on the ER, but were instead associated with an abnormal elevation of ER calcium stores. Together, our results suggest that the effects of mutant PS1 on calcium signaling are manifested predominantly at the level of the regulation of calcium stores rather than via perturbations in the numbers or activity of IP3-activated calcium release channels.
Leissring
M A
MA
Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California at Irvine, 1109 Gillespie Neuroscience Research Facility, Irvine, California 92697-4545, USA.
LaFerla
F M
FM
Callamaras
N
N
Parker
I
I
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D016296:Mutagenesis / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D053764:Presenilin-1; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D053764:Presenilin-1; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium