Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

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).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Early Presynaptic and Postsynaptic Calcium Signaling Abnormalities Mask Underlying Synaptic Depression in Presymptomatic Alzheimer's Disease Mice.
S. Chakroborty, J. Kim, C. Schneider, C. Jacobson, J. Molgo, and G. E. Stutzmann (2012)
J. Neurosci. 32, 8341-8353
   Abstract »    Full Text »    PDF »
Reply to Bezprozvanny et al.: Response to Shilling et al. (10.1074/jbc.M111.300491).
D. Shilling and J. K. Foskett (2012)
J. Biol. Chem. 287, 20470
   Full Text »    PDF »
Lack of Evidence for Presenilins as Endoplasmic Reticulum Ca2+ Leak Channels.
D. Shilling, D.-O. D. Mak, D. E. Kang, and J. K. Foskett (2012)
J. Biol. Chem. 287, 10933-10944
   Abstract »    Full Text »    PDF »
The C Terminus of Bax Inhibitor-1 Forms a Ca2+-permeable Channel Pore.
G. Bultynck, S. Kiviluoto, N. Henke, H. Ivanova, L. Schneider, V. Rybalchenko, T. Luyten, K. Nuyts, W. De Borggraeve, I. Bezprozvanny, et al. (2012)
J. Biol. Chem. 287, 2544-2557
   Abstract »    Full Text »    PDF »
Calpain-cleaved Type 1 Inositol 1,4,5-Trisphosphate Receptor (InsP3R1) Has InsP3-independent Gating and Disrupts Intracellular Ca2+ Homeostasis.
C. M. Kopil, H. Vais, K.-H. Cheung, A. P. Siebert, D.-O. D. Mak, J. K. Foskett, and R. W. Neumar (2011)
J. Biol. Chem. 286, 35998-36010
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Ca2+ Handling in Excitable Cells in Health and Disease.
G. E. Stutzmann and M. P. Mattson (2011)
Pharmacol. Rev. 63, 700-727
   Abstract »    Full Text »    PDF »
Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling.
M. Muller, C. Cardenas, L. Mei, K.-H. Cheung, and J. K. Foskett (2011)
PNAS 108, 13293-13298
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Oxidoreductin-1-Like {beta} (ERO1l{beta}) Regulates Susceptibility to Endoplasmic Reticulum Stress and Is Induced by Insulin Flux in {beta}-Cells.
C. Khoo, J. Yang, G. Rajpal, Y. Wang, J. Liu, P. Arvan, and D. A. Stoffers (2011)
Endocrinology 152, 2599-2608
   Abstract »    Full Text »    PDF »
Mutagenesis Mapping of the Presenilin 1 Calcium Leak Conductance Pore.
O. Nelson, C. Supnet, A. Tolia, K. Horre, B. De Strooper, and I. Bezprozvanny (2011)
J. Biol. Chem. 286, 22339-22347
   Abstract »    Full Text »    PDF »
Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk.
E. Zampese, C. Fasolato, M. J. Kipanyula, M. Bortolozzi, T. Pozzan, and P. Pizzo (2011)
PNAS 108, 2777-2782
   Abstract »    Full Text »    PDF »
NMDA-Mediated Ca2+ Influx Drives Aberrant Ryanodine Receptor Activation in Dendrites of Young Alzheimer's Disease Mice.
I. Goussakov, M. B. Miller, and G. E. Stutzmann (2010)
J. Neurosci. 30, 12128-12137
   Abstract »    Full Text »    PDF »
ER Calcium and Alzheimer's Disease: In a State of Flux.
M. P. Mattson (2010)
Science Signaling 3, pe10
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882