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Mol Biosyst. 2010 Sep;6(9):1640-9. doi: 10.1039/c001975e. Epub 2010 Apr 8.

Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.

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UCB 215, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.


The ER plays a fundamental role in storing cellular Ca(2+), generating Ca(2+) signals, and modulating Ca(2+) in both the cytosol and mitochondria. Genetically encoded Ca(2+) sensors can be explicitly targeted to the ER to directly define Ca(2+) levels and monitor fluxes of Ca(2+) within this organelle. In this study we use an ER-targeted Ca(2+) sensor to define both the level and dynamics of ER Ca(2+) in cells expressing mutant presenilin proteins. Growing evidence suggests the enigmatic presenilin-1 plays a role in regulating ER Ca(2+). Presenilin-1 was initially identified in a screen for genetic causes of inherited familial Alzheimer's disease (fAD). The connection between presenilin-1, calcium regulation, and Alzheimer's disease may provide the key to understanding the long-observed, but poorly understood, link between Alzheimer's disease and Ca(2+) dysregulation. In this study we examined seven fAD-causing mutations in presenilin-1 to define how they influence ER Ca(2+) levels and dynamics. We observed that some, but not all, mutations in PS1 decrease the level of Ca(2+) within the ER and this difference depends on the enzymatic activity of PS1. Two mutations tested altered the kinetics of Ca(2+) release from the ER upon ATP stimulation, resulting in faster spiking. Combined, these results indicate that mutations in PS1 can alter the balance of Ca(2+) in cells and have the potential to influence the nature of Ca(2+) signals.

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