Presenilin 1 is a direct regulator of the cardiac sarco/endoplasmic reticulum calcium pump

The gamma secretase catalytic subunit presenilin 1 (PS1) is expressed in the endoplasmic reticulum (ER) of neurons, where it regulates Ca²⁺ signaling. PS1 is also expressed in heart, but its role in regulation of cardiac Ca²⁺ transport remains unknown. Since the type 2 sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) plays a central role in cardiac Ca²⁺ homeostasis, we studied whether PS1 regulates the cardiac SERCA2a function. The experiments were conducted in an inducible human SERCA2a stable T-Rex-293 cell line transfected with fluorescently labeled PS1 and the ER Ca²⁺ sensor R-CEPIA1er. Confocal imaging showed that that PS1 is localized predominantly in the ER membrane. Fluorescent resonance energy transfer (FRET) experiments in HEK293 cells transfected with fluorescently labeled SERCA2a and PS1 revealed that the two proteins directly interact with a 1:1 stoichiometry. The functional significance of this interaction was investigated in a heterologous cellular environment using a novel approach to directly measure ER Ca²⁺ dynamics. Measurements of SERCA2a-mediated Ca²⁺ transport showed that PS1 enhanced Ca²⁺ uptake at low ER Ca²⁺ loads (<0.15 mM) and reduced uptake at high loads (>0.35 mM). The results of this study revealed that PS1 could act as an important regulator of the cardiac Ca²⁺ pump function with a complex stimulatory/inhibitory profile.