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Proc Natl Acad Sci U S A. July 18, 2000; 97 (15): 8590-3.

Calsenilin reverses presenilin-mediated enhancement of calcium signaling.

Leissring MA , Yamasaki TR , Wasco W , Buxbaum JD , Parker I , LaFerla FM .

Most cases of autosomal-dominant familial Alzheimer''s disease are linked to mutations in the presenilin genes (PS1 and PS2). In addition to modulating beta-amyloid production, presenilin mutations also produce highly specific and selective alterations in intracellular calcium signaling. Although the molecular mechanisms underlying these changes are not known, one candidate molecular mediator is calsenilin, a recently identified calcium-binding protein that associates with the C terminus of both PS1 and PS2. In this study, we investigated the effects of calsenilin on calcium signaling in Xenopus oocytes expressing either wild-type or mutant PS1. In this system, mutant PS1 potentiated the amplitude of calcium signals evoked by inositol 1,4,5-trisphosphate and also accelerated their rates of decay. We report that calsenilin coexpression reverses both of these potentially pathogenic effects. Notably, expression of calsenilin alone had no discernable effects on calcium signaling, suggesting that calsenilin modulates these signals by a mechanism independent of simple calcium buffering. Our findings further suggest that the effects of presenilin mutations on calcium signaling are likely mediated through the C-terminal domain, a region that has also been implicated in the modulation of beta-amyloid production and cell death.

PubMed ID: 10900016
PMC ID: PMC26992
Article link: Proc Natl Acad Sci U S A.
Grant support: AG16361 NIA NIH HHS , AG16573 NIA NIH HHS , GM4807 NIGMS NIH HHS , R01 AG015801 NIA NIH HHS , P50 AG016573 NIA NIH HHS , T32 AG000096 NIA NIH HHS , P50 AG005138 NIA NIH HHS , R01 AG016361 NIA NIH HHS

Genes referenced: kcnip3 tff1

External Resources:

An, 2000, Pubmed, Xenbase[+]

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