Presenilin-1 (PSEN1) is a primary component of the gamma-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease.