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


Editor's Summary

Opening the Calcium Floodgates?
Alzheimer’s disease (AD), which is the most common cause of dementia, is a neurodegenerative disorder that affects some 5 million Americans. Although most cases of AD are sporadic, an early-onset form of familial AD (FAD) has been linked to mutations in the presenilins (PSs), transmembrane proteins localized to the endoplasmic reticulum (ER). Cheung et al. investigated the effects of wild-type and mutant forms of PS on inositol trisphosphate receptor (IP3R)–mediated Ca2+ release from the ER in various different cellular systems, including human lymphoblasts derived from individuals with FAD and cortical neurons from a mouse model of FAD. They found that FAD-linked PS mutants enhanced Ca2+ release by modulating IP3R channel gating through a gain-of-function mechanism, consistent with the autosomal-dominant inheritance of FAD. FAD-linked PS mutants, but not PS mutants associated with another form of dementia, shifted IP3R channel gating to a mode in which the probability that individual channels were open after stimulation was increased, leading to exaggerated Ca2+ signals.

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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Patch-Clamp Electrophysiology of Intracellular Ca2+ Channels.
D.-O. D. Mak, H. Vais, K.-H. Cheung, and J. K. Foskett (2013)
Cold Spring Harb Protoc 2013, pdb.top066217
   Abstract »    Full Text »    PDF »
Isolating Nuclei from Cultured Cells for Patch-Clamp Electrophysiology of Intracellular Ca2+ Channels.
D.-O. D. Mak, H. Vais, K.-H. Cheung, and J. K. Foskett (2013)
Cold Spring Harb Protoc 2013, pdb.prot073056
   Abstract »    Full Text »    PDF »
Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.
E. Area-Gomez, M. del Carmen Lara Castillo, M. D. Tambini, C. Guardia-Laguarta, A. J. C. de Groof, M. Madra, J. Ikenouchi, M. Umeda, T. D. Bird, S. L. Sturley, et al. (2012)
EMBO J. 31, 4106-4123
   Abstract »    Full Text »    PDF »
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 »
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 »

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