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J. Biol. Chem. 278 (12): 10602-10612

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

IRBIT, a Novel Inositol 1,4,5-Trisphosphate (IP3) Receptor-binding Protein, Is Released from the IP3 Receptor upon IP3 Binding to the Receptor*

Hideaki AndoDagger §, Akihiro MizutaniDagger ||, Toru Matsu-uraDagger , and Katsuhiko MikoshibaDagger §||

From the Dagger  Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, the § Laboratory for Developmental Neurobiology, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, and the || Calcium Oscillation Project, International Cooperative Research Project (ICORP), Japan Science and Technology Corporation, 3-14-4 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated Ca2+ channels on intracellular Ca2+ stores. Herein, we report a novel protein, termed IRBIT (IP3R binding protein released with inositol 1,4,5-trisphosphate), which interacts with type 1 IP3R (IP3R1) and was released upon IP3 binding to IP3R1. IRBIT was purified from a high salt extract of crude rat brain microsomes with IP3 elution using an affinity column with the huge immobilized N-terminal cytoplasmic region of IP3R1 (residues 1-2217). IRBIT, consisting of 530 amino acids, has a domain homologous to S-adenosylhomocysteine hydrolase in the C-terminal and in the N-terminal, a 104 amino acid appendage containing multiple potential phosphorylation sites. In vitro binding experiments showed the N-terminal region of IRBIT to be essential for interaction, and the IRBIT binding region of IP3R1 was mapped to the IP3 binding core. IP3 dissociated IRBIT from IP3R1 with an EC50 of ~0.5 µM, i.e. it was 50 times more potent than other inositol polyphosphates. Moreover, alkaline phosphatase treatment abolished the interaction, suggesting that the interaction was dualistically regulated by IP3 and phosphorylation. Immunohistochemical studies and co-immunoprecipitation assays showed the relevance of the interaction in a physiological context. These results suggest that IRBIT is released from activated IP3R, raising the possibility that IRBIT acts as a signaling molecule downstream from IP3R.

* This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan and from RIKEN, the Brain Science Institute of Saitama, Japan.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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AB092504.

To whom correspondence should be addressed. Tel.: 81-3-5449-5319; Fax: 81-3-5449-5420; E-mail: hando@ims.u-tokyo.ac.jp.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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