Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.
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.
McCombs
Janet E
JE
UCB 215, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Gibson
Emily A
EA
Palmer
Amy E
AE
D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*
D053764:Presenilin-1; D002118:Calcium