IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO 3- cotransporter 1 (pNBC1)

Kyoko Shirakabe, Giuseppina Priori, Hideomi Yamada, Hideaki Ando, Shoko Horita, Toshiro Fujita, Ichiro Fujimoto, Akihiro Mizutani, George Seki, Katsuhiko Mikoshiba

Research output: Contribution to journalArticle

105 Citations (Scopus)

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 IP 3R 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 (kNBCI), 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.

Original languageEnglish
Pages (from-to)9542-9547
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number25
DOIs
Publication statusPublished - 2006 Jun 20

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Inositol 1,4,5-Trisphosphate Receptors
Pancreas
Carrier Proteins
Inositol 1,4,5-Trisphosphate
Xenopus
Serine
Oocytes
Phosphorylation
Kidney

Keywords

  • Acidosis
  • pH
  • Phosphorylation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO 3- cotransporter 1 (pNBC1). / Shirakabe, Kyoko; Priori, Giuseppina; Yamada, Hideomi; Ando, Hideaki; Horita, Shoko; Fujita, Toshiro; Fujimoto, Ichiro; Mizutani, Akihiro; Seki, George; Mikoshiba, Katsuhiko.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 25, 20.06.2006, p. 9542-9547.

Research output: Contribution to journalArticle

Shirakabe, Kyoko ; Priori, Giuseppina ; Yamada, Hideomi ; Ando, Hideaki ; Horita, Shoko ; Fujita, Toshiro ; Fujimoto, Ichiro ; Mizutani, Akihiro ; Seki, George ; Mikoshiba, Katsuhiko. / IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO 3- cotransporter 1 (pNBC1). In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 25. pp. 9542-9547.
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AU - Shirakabe, Kyoko

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AU - Yamada, Hideomi

AU - Ando, Hideaki

AU - Horita, Shoko

AU - Fujita, Toshiro

AU - Fujimoto, Ichiro

AU - Mizutani, Akihiro

AU - Seki, George

AU - Mikoshiba, Katsuhiko

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AB - Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated Ca2+ channels that are located on intracellular Ca2+ stores. We previously identified an IP 3R 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 (kNBCI), 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.

KW - Acidosis

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