Fig. 8. Model for the molecular mechanisms underlying regulated granular Cl^- fluxes and their actions on intragranular pH and exocytosis. (A) Replenishment of the RRP of secretory granules depends on intragranular acidification. (B) Metabolically regulated granular Cl^- uptake through an ion channel complex comprising of ClC-3 Cl^- channels (grey) and a mdr1-like 65 kDa regulatory protein (white), determines the rate of the intragranular pH decrease driven by the V-type H⁺-ATPase (black). Tolbutamide (tb), diazoxide (dz) and ADP are likely to exert their actions by interacting with the regulatory 65 kDa protein, whereas ATP, DIDS and anti-hClC-3c bind to ClC-3 directly. See text for details.