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

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.