In addition to disrupting the regulated intramembraneous proteolysis of key substrates, mutations in the presenilins also alter calcium homeostasis, but the mechanism linking presenilins and calcium regulation is unresolved. At rest, cytosolic [Ca.sup.2+] is maintained at low levels by pumping [Ca.sup.2+] into stores in the endoplasmic reticulum (ER) via the sarco ER [Ca.sup.2+]-ATPase (SERCA) pumps. We show that SERCA activity is diminished in fibroblasts lacking both PS1 and PS2 genes, despite elevated SERCA2b steady-state levels, and we show that presenilins and SERCA physically interact. Enhancing presenilin levels in Xenopus laevis oocytes accelerates clearance of cytosolic [Ca.sup.2+], whereas higher levels of SERCA2b phenocopy PS1 overexpression, accelerating [Ca.sup.2+] clearance and exaggerating inositol 1,4,5-trisphosphate--mediated [Ca.sup.2+] liberation. The critical role that SERCA2b plays in the pathogenesis of Alzheimer's disease is underscored by our findings that modulating SERCA activity alters amyloid [beta] production. Our results point to a physiological role for the presenilins in [Ca.sup.2+] signaling via regulation of the SERCA pump.