Subcellular Mechanisms of Presenilin-Mediated Enhancement of Calcium Signaling

Abstract

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 (IP 3 ). To elucidate the subcellular mechanisms underlying this enhancement, we used high resolution linescanning 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 IP 3 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 IP 3 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 IP 3 -activated calcium release channels.

γ-Secretase Activity of Presenilin 1 Regulates Acetylcholine Muscarinic Receptor-mediated Signal Transduction

“…These results are consistent with a previous study showing that the PS1 M146V mutation increases the number of ryanodine receptors in neurons and that PS1 colocalizes with ryanodine receptors at the ER level (44). It has been also shown that expression of the IP 3 receptor is not changed by FAD mutant PS1 M146V (24). We were able to reverse the increase in [Ca 2ϩ ] i peak evoked by carbachol in our FAD PS1 mutant cells by the PLC inhibitor neomycin.…”

“…Instead and in agreement with previous reports (12,23,24,40), both PS1 M146V and PS1 L250S cells showed significant increases in [Ca 2ϩ ] i upon carbachol stimulation as compared with PS1 WT and NT cells. It has been suggested that enhanced calcium signaling induced by PS1 mutants is due to elevated ER calcium content (24,40,41,42) and can be reversed by dantrolene, a specific ryanodine receptor antagonist (26,40). In this study, we show that dantrolene was able to reverse both the increased peak [Ca 2ϩ ] i values and the long tail-off effect seen in FAD PS1 mutant cells.…”

“…Serial reports by Leissring and co-workers (12,23,24) have shown that mutant PS1 enhances calcium signaling mediated by caged IP 3 in Xenopus oocytes. By imaging calcium release with high resolution line scanning confocal microscopy, they found that mutant PS1 induced an increase of ER calcium stores without affecting the number or the sensitivity of IP 3 receptors in the ER (24).…”

“…By imaging calcium release with high resolution line scanning confocal microscopy, they found that mutant PS1 induced an increase of ER calcium stores without affecting the number or the sensitivity of IP 3 receptors in the ER (24). A recent study revealed that phosphoinositide/calcium signaling is dependent on the ␥-secretase activity of PS1, because PS1 knock-out cells or cells treated with ␥-secretase inhibitors showed no calcium signals upon bradykinin stimulation (25).…”

Enhanced ROS Generation Mediated by Alzheimer's Disease Presenilin Regulation of InsP3R Ca2+ Signaling

“…Exaggerated Ca 2þ release has also been accounted for by enhanced Ca 2þ liberation from normal stores through ryanodine receptor (RyR) (10,64,71) and inositol trisphosphate receptor (InsP 3 R) (43,68) Ca 2þ release channels. The latter phenotypes have been observed both in vivo (10,65,70,71) and in vitro (17,31,35,42). Enhanced release from normal stores has been attributed either to enhanced Ca 2þ release channel expression (10,11,36,72) or, in the case of the InsP 3 R, to enhanced activity in response to its ligand InsP 3 (12,13,35).…”