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

Charles R. Shideman; Jessica L. Reinardy; Stanley A Thayer

doi:10.1016/j.neulet.2008.12.031

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

Charles R. Shideman, Jessica L. Reinardy, Stanley A Thayer

Pharmacology

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70 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	124-128
Number of pages	5
Journal	Neuroscience Letters
Volume	451
Issue number	2
DOIs	https://doi.org/10.1016/j.neulet.2008.12.031
State	Published - Feb 20 2009

Bibliographical note

Funding 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.

Keywords

Capacitative Ca entry
Dorsal root ganglion neuron
Store-operated Ca entry
γ-Secretase

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title = "γ-Secretase activity modulates store-operated Ca2+ entry into rat sensory neurons",

abstract = "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.",

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author = "Shideman, {Charles R.} and Reinardy, {Jessica L.} and Thayer, {Stanley A}",

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N2 - 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.

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