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J. Biol. Chem. 281 (48): 37111-37116

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

DANGER, a Novel Regulatory Protein of Inositol 1,4,5-Trisphosphate-Receptor Activity*

Damian B. van Rossum{ddagger}1, Randen L. Patterson{ddagger}1, King-Ho Cheung§, Roxanne K. Barrow, Viktoriya Syrovatkina{ddagger}, Gregory S. Gessell||, Scott G. Burkholder||, D. Neil Watkins||, J. Kevin Foskett§, , and Solomon H. Snyder**{ddagger}{ddagger}2

{ddagger}Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, the §Department of Physiology, University of Pennsylvania School of Medicine, University Park, Pennsylvania 16802 and The Solomon H. Snyder Department of Neuroscience, the ||Sidney Kimmel Comprehensive Cancer Center, the **Department of Pharmacology and Molecular Science, and the {ddagger}{ddagger}Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Abstract: We report the cloning and characterization of DANGER, a novel protein which physiologically binds to inositol 1,4,5-trisphosphate receptors (IP3R). DANGER is a membrane-associated protein predicted to contain a partial MAB-21 domain. It is expressed in a wide variety of neuronal cell lineages where it localizes to membranes in the cell periphery together with IP3R. DANGER interacts with IP3R in vitro and co-immunoprecipitates with IP3R from cellular preparations. DANGER robustly enhances Ca2+-mediated inhibition of IP3 RCa2+ release without affecting IP3 binding in microsomal assays and inhibits gating in single-channel recordings of IP3R. DANGER appears to allosterically modulate the sensitivity of IP3 RtoCa2+ inhibition, which likely alters IP3R-mediated Ca2+ dynamics in cells where DANGER and IP3R are co-expressed.

Received for publication September 11, 2006.

* This work was supported by United States Public Health Service Conte Center Grant MH 68830 (to S. H. S.), National Institutes of Health Grant GM/DK-56328 (to J. K. F.), and Research Scientist Award DA-00074 (to S. H. S.) and by National Research Service Award NH65090 and the Searle Foundation (to R. L. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 These authors contributed equally to the work.

2 To whom correspondence should be addressed: The Solomon H. Snyder Dept. of Neuroscience, Johns Hopkins Medical School, 725 N. Wolfe St., Baltimore, MD 21205. E-mail: ssnyder{at}jhmi.edu.

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