Inositol 1,4,5-Trisphosphate Receptor and Chromogranins A and B in Secretory Granules

Conclusions

It has been shown previously that CGA in different conformations exhibits different Ca²⁺-binding capacity and affinity (Yoo and Albanesi 1990b, 1991). In light of these observations, it is natural to think that the conformational changes of the IP₃R that occur as a result of IP₃ binding (Mignery and Südhof 1990) will be transmitted instantly to the coupled CGA and CGB in the secretory granules, causing their conformational changes. It may then be assumed that the resulting conformational changes in CGA and CGB will concomitantly result in lowering the affinity of chromogranins for Ca²⁺, thus freeing some Ca²⁺ from the proteins and making them available for release through the IP₃ channel to the cytoplasm.

In view of the fact that the secretory granules contain up to 40 mM Ca²⁺ and most (>99.9%) of it stay bound to chromogranins in the secretory granule (Bulenda and Gratzl 1985), the coupling of calcium storage proteins to the IP₃R/Ca²⁺ channel appears to reflect the efficient and intricate structural organization of an intracellular Ca²⁺ store whose Ca²⁺ storage/release function should be strictly and subtly controlled. Given the physiological needs of cells to tightly control the cellular Ca²⁺, the physical coupling of Ca²⁺ storage proteins to Ca²⁺ channels seemed to be a natural consequence. Despite the seemingly intricate structural organization inside the IP₃-sensitive Ca²⁺ stores, the amounts of Ca²⁺ released in response to a fixed amount of IP₃ vary widely in the cells (Muallem et al 1989, Meyer and Stryer 1990, Bootman et al 1992), probably due to multiple reasons, in the case of secretory granules, the amount of Ca²⁺ to be released in response to IP₃ will be determined by a combination of several factors, i.e. the IP₃ concentration introduced, the nature of tetrameric IP₃R channels formed, the types of chromogranins coupled to the IP₃R channel, and the Ca²⁺ charge states of coupled chromogranins.