The Vo sector of the vacuolar H+-ATPase is a multi-subunit complex that forms a proteolipid pore. The largest subunit in this complex is the a subunit which has four isoforms (a1-a4). The isoform(s) critical for secretory vesicle acidification has yet to be identified. Using a cell line derived from rat pheochromocytoma in which Voa1 and/or Voa2 had been down-regulated this study revealed that Voa1, and to a lesser extent, Voa2 are critical for acidifying dense-core vesicles (DCVs). The acidification defects resulting from down-regulation of Voa1 and Voa1/ Voa2 were suppressed by the expression of knockdown-resistant Voa1. Defects in DCV acidification resulted in reductions in their transmitter uptake and storage. Lastly, Ca2+-dependent peptide secretion appeared normal in Voa1 and Voa1/ Voa2 knockdown cells. . This study demonstrated that Voa1 and Voa2 cooperatively regulate dense-core vesicle acidification as well as transmitter uptake/storage, while they may not be critical for dense-core vesicle exocytosis.

The Vo sector of the vacuolar H+-ATPase is a multi-subunit complex that forms a proteolipid pore. The largest subunit in this complex is the a subunit which has four isoforms (a1-a4). The isoform(s) critical for secretory vesicle acidification has yet to be identified. Using a cell line derived from rat pheochromocytoma in which Voa1 and/or Voa2 had been down-regulated this study revealed that Voa1, and to a lesser extent, Voa2 are critical for acidifying dense-core vesicles (DCVs). The acidification defects resulting from down-regulation of Voa1 and Voa1/ Voa2 were suppressed by the expression of knockdown-resistant Voa1. Defects in DCV acidification resulted in reductions in their transmitter uptake and storage. Lastly, Ca2+-dependent peptide secretion appeared normal in Voa1 and Voa1/ Voa2 knockdown cells. . This study demonstrated that Voa1 and Voa2 cooperatively regulate dense-core vesicle acidification as well as transmitter uptake/storage, while they may not be critical for dense-core vesicle exocytosis.