Presenilin regulates capacitative calcium entry dependently and independently of γ-secretase activity

Yama Akbari, Brian D. Hitt, M. Paul Murphy, Nabil N. Dagher, Bertrand P. Tseng, Kim N. Green, Todd E. Golde, Frank M. LaFerla

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Mutations in presenilin-1 and 2 (PS) lead to increased intracellular calcium stores and an attenuation in the refilling mechanism known as capacitative calcium entry (CCE). Previous studies have shown that the mechanism by which PS modulates intracellular calcium signaling is dependent on γ-secretase activity. Although the modulation of intracellular calcium signaling can lead to alterations in CCE, it is plausible that PS can also directly affect CCE independent of the effect it exerts on intracellular stores. To investigate this possibility, we studied the effects of the dominant negative variant of PS1 known as ΔTM1-2, which lacks the first two transmembrane domains of PS1 and in which γ-secretase activity is abrogated. We demonstrate that, like other dominant negative isoforms of PS1, ΔTM1-2 expression leads to reduced intracellular calcium. However, unlike other dominant negative isoforms, ΔTM1-2 leads to a deficit rather than a potentiation of CCE. These data suggest that changes in the structural components of presenilin can modulate CCE independent of its function in γ-secretase activity and intracellular calcium stores.

Original languageEnglish
Pages (from-to)1145-1152
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume322
Issue number4
DOIs
StatePublished - Oct 1 2004

Bibliographical note

Funding Information:
We kindly thank Dr. Dennis Selkoe for providing cell lines described in Materials and methods, and Dr. Gopal Thinakaran for the presenilin antibody. We thank Maya Hatch, Karen Jansen, and Samir Shah for technical assistance, along with Drs. Ian Smith and Malcolm Leissring for helpful comments. This work was supported by grants from the NIH (AG17968, AG16573, and Medical Scientist Training Program) and the American Federation of Aging Research.

Keywords

  • APP
  • Calcium signaling
  • Capacitative calcium entry
  • Dominant negative
  • Endoplasmic reticulum
  • Intracellular stores
  • Presenilin
  • Store-operated calcium entry
  • Transmembrane domain
  • γ-Secretase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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