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Sci. Signal., 23 March 2010
Vol. 3, Issue 114, p. ra22
[DOI: 10.1126/scisignal.2000818]

RESEARCH ARTICLES

Gain-of-Function Enhancement of IP3 Receptor Modal Gating by Familial Alzheimer’s Disease–Linked Presenilin Mutants in Human Cells and Mouse Neurons

King-Ho Cheung1, Lijuan Mei1, Don-On Daniel Mak1, Ikuo Hayashi2, Takeshi Iwatsubo2, David E. Kang3, and J. Kevin Foskett1,4*

1 Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo 113-0033, Japan.
3 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
4 Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract: Familial Alzheimer’s disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca2+) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP3R) Ca2+ release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP3R channel gated. Recordings of endogenous IP3R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed that they were more likely than IP3R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca2+ signaling. These results indicate that exaggerated Ca2+ signaling through IP3R-PS interaction is a disease-specific and robust proximal mechanism in FAD.

* To whom correspondence should be addressed. E-mail: foskett{at}mail.med.upenn.edu

Citation: K.-H. Cheung, L. Mei, D.-O. D. Mak, I. Hayashi, T. Iwatsubo, D. E. Kang, J. K. Foskett, Gain-of-Function Enhancement of IP3 Receptor Modal Gating by Familial Alzheimer’s Disease–Linked Presenilin Mutants in Human Cells and Mouse Neurons. Sci. Signal. 3, ra22 (2010).

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