Novel organelle anion channels formed by chromogranin B drive normal granule maturation in endocrine cells

Abstract

All endocrine cells need an anion conductance for maturation of secretory granules. Identity of this family of anion channels has been elusive for forty years. We now show that a family of granule proteins, CHGB, serves the long-sought conductance. CHGB interacts with membranes through two amphipathic helices, and forms a chloride channel with a large conductance and high anion selectivity. Fast kinetics and high cooperativity suggest that CHGB tetramerizes to form a functional channel. Nonconducting mutants separate CHGB channel function in granule maturation from its role in granule biogenesis. In neuroendocrine cells, CHGB channel and a H+-ATPase drive normal insulin maturation inside or catecholamine loading into secretory granules. Tight membrane-association of CHGB after exocytotic release of secretory granules separates its intracellular functions from the extracellular functions accomplished by its proteolytic peptides. CHGB-null mice show impairment of granule acidification in pancreatic beta-cells due to lack of anion conductance. These findings together support that the phylogenetically conserved CHGB proteins constitute a fifth family of chloride channels that function in various endocrine cells.