Enrichment of the inositol 1,4,5-trisphosphate receptor/Ca2+ channels in secretory granules and essential roles of chromogranins

The high capacity, low affinity Ca2+ storage protein chromogranins are marker proteins of secretory granules that contain the most Ca2+ in secretory cells. Along with the abundantly expressed chromogranins, the IP3R/Ca2+ channels, the major intracellular Ca2+ channels, are also expressed in secretory granules the most. Chromogranins not only induce formation of secretory granules but also are suggested to produce the small IP3-sensitive nucleoplasmic Ca2+ store vesicles in the nucleus. Chromogranins A (CGA) and B (CGB) also directly bind the IP3Rs and activate the IP3R/Ca2+ channels at the intragranular pH 5.5. But at a near physiological pH 7.5 only CGB interacts with the IP3Rs due to stronger interaction of CGB for the IP3Rs, which is several orders of magnitude stronger than that of CGA, and activates the IP3R/Ca2+ channels. Therefore, the CGB-IP3R coupling is proposed to play key roles in the IP3-mediated Ca2+ signaling mechanisms in the cytoplasm through both secretory granules and the ER, and in the nucleus through the small IP3-sensitive nucleoplasmic Ca2+ store vesicles. Chromogranin B is further suggested to participate in transcription control and to target secretory granule components, including the IP3Rs, to newly formed secretory granules. Defects in secretory granule-related functions are directly linked to major human diseases such as Alzheimer's disease, secretory cell cancers, cystic fibrosis, acute pancreatitis, and cardiac hypertrophy. Therefore, realization of secretory granules as the major intracellular Ca2+ storage and control organelle in secretory cells promises to open new horizon in understanding the Ca2+ storage, signaling, and control mechanisms throughout the biokingdom.