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

Abstract

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 approximately 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.