Coupling of the IP₃ receptor/Ca²⁺ channel with Ca²⁺ storage proteins chromogranins A and B in secretory granules

The secretory granules of neuroendocrine cells, which function as an inositol (1,4,5)-trisphosphate-sensitive intracellular Ca²⁺ store, contain both the inositol (1,4,5)-trisphosphate receptor/Ca²⁺ channel and the high- capacity low-affinity Ca²⁺ storage proteins, chromogranins A and B. Chromogranins A and B, which exist in ~2 mM range in the secretory granules, can bind 50-100 mol of Ca²⁺/mol with dissociation constants of 2-4 mM. These proteins interact directly with the inositol (1,4,5)-trisphosphate receptor/Ca²⁺ channel at the intragranular pH 5.5, not only changing the conformation of the inositol (1,4,5)-trisphosphate receptor/Ca²⁺ channel but also modulating the channel activity. Given the homo- and heterotetrameric existence of both the inositol (1,4,5)-trisphosphate receptor/Ca²⁺ channel and chromogranins A and B, these tetrameric proteins appear to interact, thus controlling the intracellular Ca²⁺ concentration.