Inositol 1,4,5-trisphosphate receptor in chromaffin secretory granules and its relation to chromogranins.

The inositol 1,4,5-trisphosphate (IP(3))-mediated intracellular Ca(2+) releases in secretory cells play vital roles in controlling not only the intracellular Ca(2+) concentrations but also the Ca(2+)-dependent exocytotic processes. Of intracellular organelles that release Ca(2+) in response to IP(3), secretory granules stand out as the most prominent organelle and are responsible for the majority of IP(3)-dependent Ca(2+) releases in the cytoplasm of chromaffin cells. Bovine chromaffin granules were the first granules that demonstrated the IP(3)-mediated Ca(2+) release as well as the presence of the IP(3) receptor (IP(3)R) in granule membranes. Secretory granules contain all three (type 1, 2, and 3) IP(3)R isoforms, and 58-69% of total cellular IP(3)R isoforms are expressed in bovine chromaffin granules. Moreover, secretory granules contain large amounts (2-4 mM) of chromogranins and secretogranins; chromogranins A and B, and secretogranin II being the major species. Chromogranins A and B, and secretogranin II are high-capacity, low-affinity Ca(2+) binding proteins, binding 30-93 mol of Ca(2+)/mol of protein with dissociation constants of 1.5-4.0 mM. Due to this high Ca(2+) storage properties of chromogranins secretory granules contain ~40 mM Ca(2+). Furthermore, chromogranins A and B directly interact with the IP(3)Rs and modulate the IP(3)R/Ca(2+) channels, i.e., increasing the open probability and the mean open time of the channels 8- to 16-fold and 9- to 42-fold, respectively. Coupled chromogranins change the IP(3)R/Ca(2+) channels to a more ordered, release-ready state, whereby making the IP(3)R/Ca(2+) channels significantly more sensitive to IP(3).