Effects of Chromogranin A and B Association on the Anion Channel Function in the Regulated Secretory Pathway

Abstract

Chromogranins A and B (CHGA and CHGB), of the granin superfamily, are pivotal for the biogenesis, maturation and release of secretory granules in the regulated secretory pathway. They have been used as biomarkers for neuroendocrine tumors, cardiovascular diseases, and are genetically associated with Type 2 diabetes and psychiatric disorders. Although their roles in regulated secretion are conserved within the kingdom of eukaryotes, the molecular mechanisms underlying their functions inside the cells are unclear, which makes it difficult to target them for specific diseases. Chromogranin B was demonstrated to function as an anion channel in membrane. It is proposed to serve the long-sought anion conductance that is needed to shunt positive potential developed by H+-ATPase-drive proton pumping into dense-core secretory granules and maintain a more stable acidic intra-vesicular environment at pH ∼5.5. CHGA, on the other hand, was found to be in both a membrane-bound state and a soluble state. The membrane-bound CHGA alone does not conduct ions. Because CHGA and CHGB are usually present together in the secretory granules, we are studying the interactions between CHGA and CHGB in membrane, and investigate the roles of the CHGA/CHGB complex in granule maturation in neuroendocrine cells. Further, we are developing high-through screen assays to search for specific binders to the CHGA/CHGB complex and resolve the structural basis for its function using cryo-electron microscopy.