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 that PS1 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 in PS2, on intracellular calcium signaling in Xenopus oocytes. Inositol 1,4, 5-trisphosphate (IP(3))-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 mutant PS2-expressing cells in a manner dependent upon IP(3) concentration. The finding that mutations in both PS1 and PS2 modulate intracellular calcium signaling suggests that these disturbances may represent a common pathogenic mechanism of presenilin-associated FAD.
Leissring
M A
MA
Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, California 92697-4545, USA.
Parker
I
I
LaFerla
F M
FM
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics*; D008845:Microinjections; D009154:Mutation; D009865:Oocytes; D010782:Photolysis; D053766:Presenilin-2; D018075:RNA, Complementary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014466:Ultraviolet Rays; D014981:Xenopus
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D018075:RNA, Complementary; D018160:Receptors, Cytoplasmic and Nuclear; C061868:inositol 1,4,5-trisphosphate 1-(2-nitrophenyl)ethyl ester; D015544:Inositol 1,4,5-Trisphosphate