New Function of IP3 Receptor Binding Protein that Regulates pH


Ichiro Fujimoto1, Kyoko Shirakabe1, Hidetoshi Miyashita1, Katsuhiko Mikoshiba1,2,
and Keiichi Torimitsu1,3
1Divisions of Neural Signal Information NTT-IMSUT and 2Molecular Neurobiology, The Institute of Medical Science, University of Tokyo, 3Materials Science Laboratory

 The pH in the cell changes dynamically and the pH balance is regulated by carbon dioxide in vivo. It is converted into bicarbonate and transported through the transmembrane, and the cellular pH is adjusted. Bicarbonate is mainly secreted from gland cells of pancreas and works as an acid neutralizer in the stomach. Kidney cells control arterial blood pH. Several diseases or conditions such as, glaucoma, cataract, cornea disease, stunted growth, and mental retardation have been associated with the collapse of the pH balance.
 Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated Ca2+ channels located on intracellular Ca2+ stores. We previously identified an IP3R binding protein, termed IRBIT (IP3 Rbinding protein released with inositol 1,4,5-trisphosphate). Since 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. We therefore attempted to identify the target molecules of IRBIT in this study and 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 specifically bind to pNBC1 and not to bind to kNBC1 at all. IRBIT binds to the N-terminal pNBC1-specific domain, and its binding is dependent on the phosphorylation of multiple serine residues of IRBIT.
 Furthermore, an electrophysiological analysis in Xenopus oocytes revealed that pNBC1 requires co-expression of IRBIT to manifest substantial activity comparable to 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 plays an important role in pH regulation through pNBC1.
 In addition, our findings raise the possibility that the regulation through IRBIT enables NBC1 variants to play different physiological roles.

[1] K. Shirakabe et al., Proc Natl Acad Sci USA 103 (2006) 9542-9547.

Fig. 1. New concept of signal information.
Fig. 2. Activation in Xenopus oocytes.

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