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J. Biol. Chem. 281 (30): 20825-20833

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

CIB1, a Ubiquitously Expressed Ca2+-binding Protein Ligand of the InsP3 Receptor Ca2+ Release Channel*

Formula

Carl White{ddagger}, Jun Yang{ddagger}, Mervyn J. Monteiro§, , and J. Kevin Foskett{ddagger}1

Departments of {ddagger}Physiology and Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and §University of Maryland Biotechnology Institute and Medical Biotechnology Center, University of Maryland, Baltimore, Maryland 21201

Abstract: A family of Ca2+-binding proteins (CaBPs) was shown to bind to the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and gate it in the absence of InsP3, establishing them as protein ligands (Yang, J., McBride, S., Mak, D.-O. D., Vardi, N., Palczewski, K., Haeseleer, F., and Foskett, J. K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7711–7716). However, the neuronally restricted expression of CaBP and its inhibition of InsP3R-mediated Ca2+ signaling when overexpressed (Kasri, N. N., Holmes, A. M., Bultynck, G., Parys, J. B., Bootman, M. D., Rietdorf, K., Missiaen, L., McDonald, F., De Smedt, H., Conway, S. J., Holmes, A. B., Berridge, M. J., and Roderick, H. L. (2004) EMBO J. 23, 312–321; Haynes, L. P., Tepikin, A. V., and Burgoyne, R. D. (2004) J. Biol. Chem. 279, 547–555) have raised questions regarding the functional implications of this regulation. We have discovered the Ca2+-binding protein CIB1 (calmyrin) as a ubiquitously expressed ligand of the InsP3R. CIB1 binds to all mammalian InsP3R isoforms in a Ca2+-sensitive manner dependent on its two functional EF-hands and activates InsP3R channel gating in the absence of InsP3. In contrast, overexpression of CIB1 or CaBP1 attenuated InsP3R-dependent Ca2+ signaling, and in vitro pre-exposure to CIB1 reduced the number of channels available for subsequent stimulation by InsP3. These results establish CIB1 as a ubiquitously expressed activating and inhibiting protein ligand of the InsP3R.


Received for publication March 7, 2006. Revision received May 23, 2006.

* This work was supported by Grant R01-GM056328 from the National Institutes of Health (to J. K. F.). 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.


Formula

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

1 To whom correspondence should be addressed: Dept. of Physiology, University of Pennsylvania, B39 Anatomy-Chemistry Bldg., 414 Guardian Dr., Philadelphia, PA 19104-6085; Tel.: 215-898-1354; Fax: 215-573-6808; E-mail: foskett{at}mail.med.upenn.edu.


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