gamma-Secretase activity modulates store-operated Ca2+ entry into rat sensory neurons.
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.
Shideman
Charles R
CR
Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, United States.
Reinardy
Jessica L
JL
Thayer
Stanley A
SA
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium; C000543:cyclopiazonic acid