Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

doi:10.1083/jcb.149.4.793

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© The Rockefeller University Press, 0021-9525/2000/5/793/ $5.00
The Journal of Cell Biology, Volume 149, Number 4, May 15, 2000 793-798

Brief Report

Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

Malcolm A. Leissring^a, Yama Akbari^a, Christopher M. Fanger^b, Michael D. Cahalan^b, Mark P. Mattson^c, and Frank M. LaFerla^a
^a Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and Institute for Brain Aging and Dementia, University of California Irvine, Irvine, California 92697-4545
^b Department of Physiology and Biophysics, University of California Irvine, Irvine, California 92697-4561
^c Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224

Correspondence to: Frank M. LaFerla, Department of Neurobiology and Behavior, University of California Irvine, 1109 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4545. Tel:(949) 824-1232 Fax:(949) 824-7356 E-mail:laferla{at}uci.edu.

Dysregulation of calcium signaling has been causally implicatedin brain aging and Alzheimer's disease. Mutations in the presenilingenes (PS1, PS2), the leading cause of autosomal dominant familialAlzheimer's disease (FAD), cause highly specific alterationsin intracellular calcium signaling pathways that may contributeto the neurodegenerative and pathological lesions of the disease.To elucidate the cellular mechanisms underlying these disturbances,we studied calcium signaling in fibroblasts isolated from mutantPS1 knockin mice. Mutant PS1 knockin cells exhibited a markedpotentiation in the amplitude of calcium transients evoked byagonist stimulation. These cells also showed significant impairmentsin capacitative calcium entry (CCE, also known as store-operatedcalcium entry), an important cellular signaling pathway whereindepletion of intracellular calcium stores triggers influx ofextracellular calcium into the cytosol. Notably, deficits inCCE were evident after agonist stimulation, but not if intracellularcalcium stores were completely depleted with thapsigargin. Treatmentwith ionomycin and thapsigargin revealed that calcium levelswithin the ER were significantly increased in mutant PS1 knockincells. Collectively, our findings suggest that the overfillingof calcium stores represents the fundamental cellular defectunderlying the alterations in calcium signaling conferred bypresenilin mutations.

Key Words: Alzheimer's disease, endoplasmic reticulum, phosphoinositidesignaling, store-operated calcium channel, store-operated calciumentry

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