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

Abstract

Perturbed Ca2+ homeostasis is a common molecular consequence of familial Alzheimer's disease-linked presenilin mutations. We report here the molecular interaction of the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a penta-EF-hand Ca2+-binding protein that serves as a modulator of the ryanodine receptor intracellular Ca2+ channel. The association of endogenous sorcin and PS2 was demonstrated in cultured cells and human brain tissues. Membrane-associated sorcin and a subset of the functional PS2 complexes were co-localized to a novel subcellular fraction that is distinctively positive for calcineurin B. Sorcin was found to interact with PS2 endoproteolytic fragments but not full-length PS2, and the sorcin/PS2 interaction was greatly enhanced by treatment with the Ca2+ ionophore A23187. Our findings 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.