Molecular Requirements of Chromogranin B for the Long-sought Anion Shunter of Regulated Secretion

Highlights: Loss of CHGB channel functions impairs secretory granule acidification in neuroendocrine cells, which necessitates anion shunt conduction. CHGBΔMIF, a mutant unable to form a functional Cl channel, exerts negative dominance on endogenous CHGB and results in granule deacidification in cultured cells. Neither CLC-3 & -5 nor ANO-1 & -2 participate in the CHGB-mediated granule acidification. Clcn3 knockout effects on regulated secretion can be attributed to its functions in endosomal and endolysosomal compartments. Primary β-cells exhibit persistent granule deacidification, presenting a unifying mechanism for disparate mouse phenotypes: hyperproinsulinemia, near abrogation of 2 phase insulin release after glucose challenge and diminution of monoamine contents in chromaffin granules.