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 Ca²⁺ 
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 γ-secretase inhibitor or 
dominant negative γ-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.