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, Frank M. LaFerla

Research output: Contribution to journalArticlepeer-review

195 Scopus citations

Abstract

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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)1107-1116
Number of pages10
JournalJournal of Cell Biology
Volume181
Issue number7
DOIs
StatePublished - Jun 30 2008
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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