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.
Bibliographical noteFunding Information:
Grants from the NSF (IOS0814549) and NIH (DA007304, DA011806) supported this work. We thank Dr. D. Selkoe for generously providing us with presenilin expression vectors and we thank Dr. S. Hayward for kindly providing us with the CBF1 luciferase reporter plasmid.
- Capacitative Ca entry
- Dorsal root ganglion neuron
- Store-operated Ca entry