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bioRxiv · 10.1101/302828

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

Yadav, G.·Zheng, H.·Yang, Q.·Douma, L.·Annamalai, M.·Bloom, L.·Mathews, C.·Jiang, Q.-X.
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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 CHGBs 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. CHGBs 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.

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Yadav, G., Zheng, H., Yang, Q., Douma, L., Annamalai, M., Bloom, L., Mathews, C., Jiang, Q.-X.. 2018-04-17. Novel organelle anion channels formed by chromogranin B drive normal granule maturation in endocrine cells. https://doi.org/10.1101/302828

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