Editors' ChoiceCalcium signaling

New IP3 Receptor Partner?

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Science's STKE  25 Mar 2003:
Vol. 2003, Issue 175, pp. tw121-TW121
DOI: 10.1126/stke.2003.175.tw121

The inositol 1,4,5-trisphosphate receptor (IP3R) is a ligand-gated ion channel that mediates release of Ca2+ from intracellular stores in response to stimuli that promote hydrolysis of phosphatidylinositol 4,5-bisphosphate. In this crucial role, the channel is, of course, highly regulated, and this occurs in part through interaction with other proteins. In a screen for new interaction partners of the IP3 receptor, Ando et al. identified a protein they call IRBIT (for IP3R-binding protein released with inositol 1,4,5-trisphosphate), which has a number of intriguing properties. IRBIT looks like S-adenosylhomocysteine hydrolase, the enzyme that cleaves S-adenosylhomocysteine to form adenosine and homocysteine, but the authors could find no such enzymatic activity of IRBIT. IRBIT from extracts of rat cerebellar microsomes bound to the NH2-terminal portion of the IP3R in vitro, and the interaction was localized to the IP3-binding region of the IP3R. IRBIT contains numerous potential phosphorylation sites, and treatment of extracts with alkaline phosphatase prevented interaction of IRBIT with the IP3R. Immunoprecipitation of proteins from lysates of mouse cerebellum with an antibody to IRBIT provided evidence that the IP3R and IRBIT interact in vivo. The authors' original screen selected for proteins whose interaction with the IP3R was altered by binding of IP3, and further analysis of in vitro binding showed that concentrations of IP3 estimated to be in the physiological range displaced IRBIT bound to the IP3R. The authors note that IRBIT displaced from the IP3R upon binding of IP3 could generate another signal independent of the well-characterized Ca2+ mobilization. Alternative roles for IRBIT in modulating channel activity, regulating susceptibility of the receptor to proteolytic degradation, or as a linker or scaffold are also possible.

H. Ando, A. Mizutani, T. Matsu-ura, K. Mikoshiba, IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor. J. Biol. Chem. 278, 10602-10612 (2003). [Abstract] [Full Text]

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