Up-regulation of inositol 1,4,5-trisphosphate receptor type 1 is responsible for a decreased endoplasmic-reticulum Ca 2+ content in presenilin double knock-out cells

Abstract

Presenilins (PS) are proteins involved in the pathogenesis of autosomal-dominant familial cases of Alzheimer's disease. Mutations in PS are known to induce specific alterations in cellular Ca 2+ signaling which might be involved in the pathogenesis of neurodegenerative diseases. Mouse embryonic fibroblasts (MEF) deficient in PS1 and PS2 (PS DKO) as well as the latter rescued with PS1 (Rescue), were used to investigate the underlying mechanism of these alterations in Ca 2+ signaling. PS DKO cells were characterized by a decrease in the [Ca 2+] ER as measured by ER-targeted aequorin luminescence and an increased level of type 1 inositol 1,4,5-trisphosphate receptor (IP 3R1). The lower [Ca 2+] ER was associated with an increase in a Ca 2+ leak from the ER. The increased IP 3R1 expression and the concomitant changes in ER Ca 2+ handling were reversed in the Rescue cells. Moreover using RNA-interference mediated reduction of IP 3R1 we could demonstrate that the up-regulation of this isoform was responsible for the increased Ca 2+ leak and the lowered [Ca 2+] ER in PS DKO cells. Finally, we show that the decreased [Ca 2+] ER in PS DKO cells was protective against apoptosis.