Genetic deletion or mutations of presenilin genes (PS1/PS2) cause familial Alzheimer's disease and calcium (Ca2+) signaling abnormalities. PS1/PS2 act as endoplasmic reticulum (ER) Ca2+ leak channels that facilitate passive Ca2+ leak across ER membrane. Studies with PS1/PS2 double knockout (PS1/PS2-DKO) mouse embryonic fibroblasts showed that PS1/PS2 were responsible for 80% of passive Ca2+ leak from the lumen of endoplasmic reticulum to cytosol. Transient transfection of the wild type PS1 expression construct increased cytoplasmic Ca2+ as a result of Ca2+ leak across ER membrane whereas the FADPS1 (PS1-M146V) mutation construct alone or in combination with the wild type PS1 expression construct abrogated Ca2+ leak in SK-N-SH cells. Inhibition of basal c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK-N-SH cells (Lee and Das 2008). In this report we also showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited passive Ca2+ leak across ER membrane which could be rescued by expressing PS1 wild type and not by expressing FADPS1 (PS1-M146V) under a SP600125 non-responsive promoter. Treatment of SK-N-SH cells with SP600125 also triggered InsP3R-mediated Ca 2+ release from the ER by addition of 500 nM bradykinin, an agonist of InsP3 receptor (InsP3R1) without changing the expression of InsP3R1. This data confirms that SP600125 increases the Ca2+ store in the ER by inhibiting PS1-mediated Ca2+ leak across ER membrane. p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca2+ leak across ER membrane in SK-N-SH cells but ÎÂ3-secretase inhibitor or dominant negative ÎÂ3-secretase-specific PS1 mutant (PS1-D257A) had no significant effect. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca2+ leak channels to regulate both ER and cytoplasmic Ca2+ levels and may potentially control Ca2+-signaling function of PS1. Presenilin 1 (PS1) protein acts as ER Ca2+ leak channels that facilitate passive Ca2+ leak from ER lumen to cytosol. Suppression of PS1 transcription by JNK-specific inhibitor SP600125, p53, ZNF237, and CHD3 inhibits the function ER Ca 2+ leak channels to regulate both ER and cytoplasmic Ca2+ in SK-N-SH cells. Mutations in the PS1 gene cause early onset familial Alzheimer's disease (FAD). FAD-PS1 mutations abrogate PS1-mediated ERCa 2+ channel activity resulting in neurodegeneration in FAD patients. Therefore, inhibition of transcription of the FADPS1 gene by SP600125, p53, ZNF237, and CHD3 may potentially rescue ERCa2+ channel activity to prevent neuronal apoptosis in FAD patients.