Presenilin-Mediated Modulation of Capacitative Calcium Entry

We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a rol...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2000-09, Vol.27 (3), p.561-572
Main Authors: Yoo, Andrew S, Cheng, Isaac, Chung, Sungkwon, Grenfell, Tallessyn Z, Lee, Hanmi, Pack-Chung, Eunju, Handler, Melissa, Shen, Jie, Xia, Weiming, Tesco, Giuseppina, Saunders, Aleister J, Ding, Kai, Frosch, Matthew P, Tanzi, Rudolph E, Kim, Tae-Wan
Format: Article
Language:English
Subjects:
Alzheimer Disease - physiopathology
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Calcium Channels - drug effects
Calcium Channels - metabolism
Calcium Channels, L-Type - drug effects
Calcium Channels, L-Type - metabolism
Calcium Channels, N-Type - drug effects
Calcium Channels, N-Type - metabolism
Cells, Cultured
Cytochalasin D - pharmacology
Humans
Imidazoles - pharmacology
Ion Transport - drug effects
Ion Transport - genetics
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membrane Proteins - pharmacology
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Neurons - cytology
Neurons - metabolism
Patch-Clamp Techniques
Peptide Fragments - metabolism
Presenilin-1
Presenilin-2
Transfection
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Summary:We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a role for PS1 in the modulation of CCE. In contrast, familial Alzheimer's disease (FAD)–linked mutant PS1 or PS2 significantly attenuated CCE and store depletion–activated currents. While inhibition of CCE selectively increased the amyloidogenic amyloid β peptide (Aβ42), increased accumulation of the peptide had no effect on CCE. Thus, reduced CCE is most likely an early cellular event leading to increased Aβ42 generation associated with FAD mutant presenilins. Our data indicate that the CCE pathway is a novel therapeutic target for Alzheimer's disease.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(00)00066-0