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Published online June 30, 2008
doi:10.1083/jcb.200706171
The Journal of Cell Biology, Vol. 181, No. 7, 1107-1116
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Green et al.
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Article

 SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β production

Kim N. Green, Angelo Demuro, Yama Akbari, Brian D. Hitt, Ian F. Smith, Ian Parker, and Frank M. LaFerla

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697

Correspondence to Frank M. LaFerla: laferla{at}uci.edu

In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic Ca2+ is maintained at low levels by pumping Ca2+ into stores in the endoplasmic reticulum (ER) via the sarco ER Ca2+-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic Ca2+, whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating Ca2+ clearance and exaggerating inositol 1,4,5-trisphosphate–mediated Ca2+ liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid β production. Our results point to a physiological role for the presenilins in Ca2+ signaling via regulation of the SERCA pump.

K.N. Green and A. Demuro contributed equally to this paper.

Abbreviations used in this paper: Aβ, amyloid β; AD, Alzheimer's disease; AICD, APP intracellular domain; APP, amyloid precursor protein; CCE, capacitative Ca2+ entrance; FAD, familial AD; IP3, inositol 1,4,5-trisphosphate; MEF, mouse embryonic fibroblast; nAChR, nicotinic acetylcholine receptor; pcDNA, pseudo-cDNA; PSDKO, presenilin double knockout; SERCA, sarco ER Ca2+-ATPase.


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