Cell Physiology

DANGER, New Regulator of IP3R Calcium-Release Channel

Science's STKE  05 Dec 2006:
Vol. 2006, Issue 364, pp. tw408
DOI: 10.1126/stke.3642006tw408

The inositol 1,4,5-trisphosphate receptor (IP3R) functions as a sensor for the second messenger IP3 and as a channel protein that allows release of Ca2+ from intracellular stores in response to activated receptors that are linked to production of IP3. However, there are some 2000 extra amino acids in the large IP3R protein in between the region that confers IP3 binding and the Ca2+ channel itself, and a number of proteins have been identified that interact with the IP3R in this region to regulate its function. Van Rossum et al. used a yeast 2-hybrid screen to search for other IP3R-interacting proteins in mammalian cDNA libraries and identified a new one they call DANGER. The authors confirmed interaction of the endogenous proteins by immunoprecipitation from cultured PC12 and showed colocalization with IP3Rs near the plasma membrane by immunofluorescence microscopy. Addition of glutathione S-transferase­-tagged DANGER to microsomal fractions from COS7 cells expressing transfected IP3R enhanced the sensitivity of the channel to inhibitory feedback by Ca2+. Normally, supraphysiological concentrations of Ca2+ are needed to decrease IP3-dependent release of Ca2+ through the receptor, but when DANGER was present, moderate concentrations of Ca2+ (0.8 to 3.8 μM) almost abolished Ca2+ release. Single-channel recordings of IP3R activity showed that DANGER reduced the channel open probability by decreasing the opening rate of the channel. The authors propose that DANGER appears to cause allosteric regulation of the IP3R that enhances the Ca2+ sensitivity of the receptor such that Ca2+ becomes a major regulator of the IP3R in cells expressing DANGER.

D. B. van Rossum, R. L. Patterson, K.-H. Cheung, R. K. Barrow, V. Syrovatkina, G. S. Gessell, S. G. Burkholder, D. N. Watkins, J. K. Foskett, S. H. Snyder, DANGER, a novel regulatory protein of inositol 1,4,5-trisphosphate-receptor activity. J. Biol. Chem. 281, 37111-37116 (2006). [Abstract] [Full Text]