Chromogranin B Serves the Long-Sought-After Anion Conductance in Regulated Secretion

Abstract

Regulated secretion is an intracellular pathway that empowers stimulus-controlled release of bioactive molecules in all endocrine cells. An anion channel has been known to be required for acidification and maturation of the secretory granules for forty years. But the identity of this anion conductance remains elusive. We now show that chromogranin B (CHGB), a well-conserved protein in the regulated secretory pathway, forms the long-sought-after anion-selective channel in the membranes of secretory granules. In planar lipid bilayers and lipid vesicles CHGB alone forms a pH- and Ca2+-sensitive anion channel with anion selectivity higher than other known chloride channels. Two amphipathic helical domains mediate membrane insertion and channel formation. Expression of channel-defective mutants in CHGB knockdown cells separates its role in granule maturation from that in granule biogenesis and demonstrates the necessity of the CHGB anion conductance to granule acidification and cargo maturation. Together our data demonstrate that phylogenetically conserved CHGBs constitute a new family of organelle chloride channels in endocrine cells.