New IP 3 Receptor Partner?

Abstract

The inositol 1,4,5-trisphosphate receptor (IP 3 R) is a ligand-gated ion channel that mediates release of Ca 2+ 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 IP 3 receptor, Ando et al. identified a protein they call IRBIT (for IP 3 R-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 NH 2 -terminal portion of the IP 3 R in vitro, and the interaction was localized to the IP 3 -binding region of the IP 3 R. IRBIT contains numerous potential phosphorylation sites, and treatment of extracts with alkaline phosphatase prevented interaction of IRBIT with the IP 3 R. Immunoprecipitation of proteins from lysates of mouse cerebellum with an antibody to IRBIT provided evidence that the IP 3 R and IRBIT interact in vivo. The authors' original screen selected for proteins whose interaction with the IP 3 R was altered by binding of IP 3 , and further analysis of in vitro binding showed that concentrations of IP 3 estimated to be in the physiological range displaced IRBIT bound to the IP 3 R. The authors note that IRBIT displaced from the IP 3 R upon binding of IP 3 could generate another signal independent of the well-characterized Ca 2+ 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]