Abstract
Presenilin-1 is required for gamma-secretase activity, which participates in Notch receptor processing, the pathogenesis of Alzheimer's disease and the modulation of Ca(2+) signaling. We tested the hypothesis that gamma-secretase proteolytic activity modulates store-operated Ca(2+) entry (SOCE) in rat dorsal root ganglion (DRG) neurons. Depletion of intracellular Ca(2+) stores by blocking the endoplasmic reticulum (ER) Ca(2+) pump with cyclopiazonic acid (CPA) evoked a transient increase in [Ca(2+)](i) but no sustained Ca(2+) influx. However, in cells expressing a dominant negative presenilin-1 mutant (PS1-D257A), gamma-secretase activity was inhibited and treatment with CPA evoked sustained Ca(2+) influx. Similarly, pharmacologic inhibition of gamma-secretase with DAPT for 48h enhanced SOCE. SKF96365, an inhibitor of store-operated channels, blocked SOCE in cells expressing PS1-D257A. Thus, gamma-secretase proteolytic activity regulates a SOCE pathway in sensory neurons.