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PNAS 103 (25): 9542-9547

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3– cotransporter 1 (pNBC1)

Kyoko Shirakabe*, Giuseppina Priori*, Hideomi Yamada{dagger}, Hideaki Ando{ddagger}, Shoko Horita{dagger}, Toshiro Fujita{dagger}, Ichiro Fujimoto*,§, Akihiro Mizutani, George Seki{dagger}, and Katsuhiko Mikoshiba*,{ddagger},§,¶,||

Divisions of *Neural Signal Information NTT-IMSUT, and Molecular Neurobiology, Institute of Medical Science,University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; {dagger}Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8635, Japan; {ddagger}Laboratory for Developmental Neurobiology, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; and ||Calcium Oscillation Project, International Cooperative Research Project, Japan Science and Technology Corporation, 3-14-4 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 8, 2006

Received for publication March 20, 2006.

Abstract: Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated Ca2+ channels that are located on intracellular Ca2+ stores. We previously identified an IP3R binding protein, termed IP3R binding protein released with IP3 (IRBIT). Because IRBIT is released from IP3R by physiological concentrations of IP3, we hypothesized that IRBIT is a signaling molecule that is released from IP3R and regulates downstream target molecules in response to the production of IP3. Therefore, in this study, we attempted to identify the target molecules of IRBIT, and we succeeded in identifying Na+/HCO3– cotransporter 1 (NBC1) as an IRBIT binding protein. Of the two major splicing variants of NBC1, pancreas-type NBC1 (pNBC1) and kidney-type NBC1 (kNBC1), IRBIT was found to bind specifically to pNBC1 and not to bind to kNBC1. IRBIT binds to the N-terminal pNBC1-specific domain, and its binding depends on the phosphorylation of multiple serine residues of IRBIT. Also, an electrophysiological analysis in Xenopus oocytes revealed that pNBC1 requires coexpression of IRBIT to manifest substantial activity comparable with that of kNBC1, which displays substantial activity independently of IRBIT. These results strongly suggest that pNBC1 is the target molecule of IRBIT and that IRBIT has an important role in pH regulation through pNBC1. Also, our findings raise the possibility that the regulation through IRBIT enables NBC1 variants to have different physiological roles.

Key Words: pH • acidosis • phosphorylation

Author contributions: K.S., I.F., and K.M. designed research; K.S., G.P., H.Y., H.A., S.H., T.F., I.F., A.M., and G.S. performed research; and K.S. and G.S. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

§To whom correspondence may be addressed. E-mail: mikosiba{at}ims.u-tokyo.ac.jp or fujimoto{at}ims.u-tokyo.ac.jp

© 2006 by The National Academy of Sciences of the USA

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