γ-Secretase activity modulates store-operated Ca2+ entry into rat sensory neurons

Presenilin-1 is required for γ-secretase activity, which participates in Notch receptor processing, the pathogenesis of Alzheimer's disease and the modulation of Ca2+ signaling. We tested the hypothesis that γ-secretase proteolytic activity modulates store-operated Ca2+ entry (SOCE) in rat dorsal root ganglion (DRG) neurons. Depletion of intracellular Ca2+ stores by blocking the endoplasmic reticulum (ER) Ca2+ pump with cyclopiazonic acid (CPA) evoked a transient increase in [Ca2+]i but no sustained Ca2+ influx. However, in cells expressing a dominant negative presenilin-1 mutant (PS1-D257A), γ-secretase activity was inhibited and treatment with CPA evoked sustained Ca2+ influx. Similarly, pharmacologic inhibition of γ-secretase with DAPT for 48 h enhanced SOCE. SKF96365, an inhibitor of store-operated channels, blocked SOCE in cells expressing PS1-D257A. Thus, γ-secretase proteolytic activity regulates a SOCE pathway in sensory neurons.