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J. Biol. Chem. 275 (19): 14440-14445

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

J Biol Chem, Vol. 275, Issue 19, 14440-14445, May 12, 2000

Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor*

Eunju Pack-ChungDagger , Marian B. Meyers§, Warren P. PettingellDagger , Robert D. MoirDagger , Amy M. Brownawell||, Isaac ChengDagger **, Rudolph E. TanziDagger , and Tae-Wan KimDagger Dagger Dagger

From the Dagger  Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, the § Department of Medicine, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York 10029, and the || Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908

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.

* This work was supported in part by NIA grants from the National Institutes of Health and the Alzheimer's Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Kenner Fellow of the American Heart Association.

** Howard Hughes Medical Institute Medical Student Training Fellow.

Dagger Dagger Recipient of the Partners Investigator (Nesson) award. To whom correspondence should be addressed. Tel.: 617-726-3739; Fax: 617-726-5677; E-mail: kim@helix.mgh.harvard.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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