Presenilin 1 is a direct regulator of the cardiac sarco/endoplasmic reticulum calcium pump. (November 2021)

• Record Type: Journal Article
• Authors: Bovo, Elisa; Nikolaienko, Roman; Kahn, Daniel; Cho, Ellen; Robia, Seth L.; Zima, Aleksey V.
• Is Part Of: Cell calcium. Volume 99(2021)
• Publication Date: 2021-11
• Subjects: Ca2+ pump -- Presenelin 1 -- Ca2+ transport -- FRET -- Endoplasmic reticulum -- HEK293 cells; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2021.102468
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: Presenilin 1 directly interacts with SERCA2a. Direct measurement of ER Ca 2+ shows that PS1 directly regulates SERCA2a function. PS1 regulates SERCA2a with a complex stimulatory/inhibitory profile that is [Ca 2+ ]ER dependent. Abstract: The gamma secretase catalytic subunit presenilin 1 (PS1) is expressed in the endoplasmic reticulum (ER) of neurons, where it regulates Ca 2+ signaling. PS1 is also expressed in heart, but its role in regulation of cardiac Ca 2+ transport remains unknown. Since the type 2 sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2a) plays a central role in cardiac Ca 2+ 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 Ca 2+ 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 Ca 2+ dynamics. Measurements of SERCA2a-mediated Ca 2+ transport showed that PS1 enhanced Ca 2+ uptake at low ER Ca 2+ 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 Ca 2+ pump function with a complex stimulatory/inhibitory profile. Graphical abstract: Image, graphical abstract