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 protein, CHGB, serves the long-sought conductance. CHGB interacts with membranes through two amphipathic helices, and forms a chloride channel with large conductance and high anion selectivity. Fast kinetics and high cooperativity suggest that CHGB tetramerizes to form a functional channel. Nonfunctional mutants separate CHGB’s function in granule maturation from that in granule biogenesis. In neuroendocrine cells, CHGB channel and a H⁺-ATPase drives normal insulin maturation inside or dopamine loading into secretory granules. CHGB’s tight membrane-association after exocytotic release of secretory granules separates its intracellular function from extracellular functions of its proteolytic peptides. CHGB-null mice show consistent impairment of granule acidification in pancreatic beta-cells. These findings together support that the phylogenetically conserved CHGB proteins constitute a new family of organelle chloride channels in the regulated secretory pathway among various endocrine cells.