Editors' ChoiceCalcium signaling

Enhancing Channel Activity

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Science Signaling  01 Jul 2008:
Vol. 1, Issue 26, pp. ec238
DOI: 10.1126/scisignal.126ec238

Alzheimer’s disease (AD) is associated with the accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the brain, but whether Aβ is responsible for triggering AD is unclear. Excessive Ca2+ signaling, which is very toxic to neurons, is another potential culprit. The γ secretase complex, whose core components are the presenilin (PS) proteins, processes the amyloid precursor protein (APP) to produce Aβ. Cells containing mutant PS proteins associated with familial AD (FAD) exhibit excessive Ca2+ signaling. Because the inositol 1,4,5-trisphosphate receptor (IP3R) is the channel responsible for Ca2+ egress from the endoplasmic reticulum (ER), Cheung et al. investigated a role for PS proteins in modulating IP3R activity. Coimmunoprecipitation assays showed the physical association of either wild-type or FAD PS proteins with IP3Rs in mouse brain lysates. Single-channel patch-clamp current recordings showed that basal and IP3-stimulated channel activity in chick DT40 cells overexpressing FAD PS proteins was enhanced compared with that in cells expressing wild-type PS proteins and was more sensitive to lower concentrations of IP3. The increased Ca2+ flux in FAD PS–expressing cells was associated with the IP3R being in an open state for longer durations than was the case in wild-type PS-expressing cells. Similar electrophysiological experiments showed that FAD PS1 enhanced IP3R-mediated Ca2+ signaling in transfected mouse brain cortical neurons. Although overexpression of FAD PS1 increased Aβ production by APP-expressing DT40 cells compared with that observed when wild-type PS1 was overexpressed, this enhancement of APP processing was blocked in DT40 cells deficient in all IP3R isoforms. Together, these data suggest that increased Ca2+ signaling through mutant PS-mediated enhancement of IP3R activity may play a role in the pathogenesis of AD.

K.-H. Cheung, D. Shineman, M. Müller, C. Cárdenas, L. Mei, J. Yang, T. Tomita, T. Iwatsubo, V. M.-Y. Lee, J. K. Foskett, Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58, 871-883 (2008). [PubMed]

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