Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor

Perturbed Ca2+ homeostasis is a common molecular consequence of familial Al zheimer's disease-linked presenilin mutations. We report here the molecular interaction of the large hydrophilic loop region of presenilin 2 (PS2) wit h sorcin, a penta-EF-hand Ca2+-binding protein that serves as a modulator o f the ryanodine receptor intracellular Ca2+ channel. The association of end ogenous sorcin and PS2 was demonstrated in cultured cells and human brain t issues. Membrane-associated sorcin and a subset of the functional PS2 compl exes were co-localized to a novel subcellular fraction that is distinctivel y positive for calcineurin B. Sorcin was found to interact with PS2 endopro teolytic fragments but not full-length PS2, and the sorcin/PS2 interaction was greatly enhanced by treatment with the Ca2+ ionophore A23187. Our findi ngs reveal a molecular link between PS2 and intracellular Ca2+ channels (i. e. ryanodine receptor) and substantiate normal and/or pathological roles of PS2 in intracellular Ca2+ homeostasis.