Inositol 1,4,5-trisphosphate receptor and chromogranins A and B in secretory granules. Co-localization and functional coupling.

Abstract

ConclusionsIt 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.