The Ion Channel Function of Mouse Chromogranin B

Abstract

Chromogranins are known to play fundamentally important roles in the biogenesis, acidification and maturation as well as the regulated release of secretory granules in almost all endocrine cells. Elevated level of chromogranin A and B has been biomarkers for multiple different neuroendocrine tumors. The function of chromogranins in the regulated secretory pathway is conserved in the whole kingdom of eukaryote. Even though immuno-histochemical data and biochemical analysis have provided key evidence that these proteins are important for sorting of granule-specific cargos and for the generation of specific peptide hormones after processing and release of the granules, the exact function of the chromogranins besides being a low-affinity calcium binder and a potential interaction partner with the IP3R remains unclear. We are using mouse chromogranin B as our model system in order to understand some of the key functions of chromogranins. We did not detect strong direct interactions between chromogranin B and the type 1 IP3R. Instead we observed strong calcium-dependent aggregation of chromogranin B. When reconstituted in liposomes, chromogranin B formed pH and calcium-regulated conductance, and the channels appear to conduct F- and Cl- but not formate, acetate or citrate. Our biochemical data demonstrated that a short fragment close to the C-terminus of the protein is the only one capable of membrane binding. Our working model is that chromogranin B not only induces biogenesis of secretory granules, but its anionic conductance functions to support the continued acidification of the luminal side of the granules, which is critical for the proper processing of the cargos inside.