Inositol 1,4,5-Trisphosphate Receptor in Chromaffin Secretory Granules and Its Relation to Chromogranins

摘要

The inositol 1,4,5-trisphosphate (IP₃)-mediated intracellular Ca2+ releases in secretory cells play vital roles in controlling not only the intracellular Ca2+ concentrations but also the Ca2+-dependent exocytotic processes. Of intracellular organelles that release Ca2+ in response to IP₃, secretory granules stand out as the most prominent organelle and are responsible for the majority of IP₃-dependent Ca2+ releases in the cytoplasm of chromaffin cells. Bovine chromaffin granules were the first granules that demonstrated the IP₃-mediated Ca2+ release as well as the presence of the IP₃ receptor (IP₃R) in granule membranes. Secretory granules contain all three (type 1, 2, and 3) IP₃R isoforms, and 58–69% of total cellular IP₃R 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 Ca2+ binding proteins, binding 30–93 mol of Ca2+/mol of protein with dissociation constants of 1.5–4.0 mM. Due to this high Ca2+ storage properties of chromogranins secretory granules contain ~40 mM Ca2+. Furthermore, chromogranins A and B directly interact with the IP₃Rs and modulate the IP₃R/Ca2+ 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 IP₃R/Ca2+ channels to a more ordered, release-ready state, whereby making the IP₃R/Ca2+ channels significantly more sensitive to IP₃.