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First published online 17 October 2006
doi: 10.1242/jcs.03234

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The a3 isoform of V-ATPase regulates insulin secretion from pancreatic ß-cells

¹ Department of Biochemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyotanabe 610-0395, Japan
² Division of Biological Sciences, Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan
³ Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
⁴ Futai Special Laboratory, Microbial Chemistry Research Center, CREST, Japan Science and Technology Agency, Tokyo 141-0021, Japan

^* Author for correspondence (e-mail: kwada{at}dwc.doshisha.ac.jp)

Accepted 30 August 2006

Vacuolar-type H⁺-ATPase (V-ATPase) is a multi-subunit enzyme that has important roles in the acidification of a variety of intracellular compartments and some extracellular milieus. Four isoforms for the membrane-intrinsic subunit (subunit a) of the V-ATPase have been identified in mammals, and they confer distinct cellular localizations and activities on the proton pump. We found that V-ATPase with the a3 isoform is highly expressed in pancreatic islets, and is localized to membranes of insulin-containing secretory granules in ß-cells. oc/oc mice, which have a null mutation at the a3 locus, exhibited a reduced level of insulin in the blood, even with high glucose administration. However, islet lysates contained mature insulin, and the ratio of the amount of insulin to proinsulin in oc/oc islets was similar to that of wild-type islets, indicating that processing of insulin was normal even in the absence of the a3 function. The insulin contents of oc/oc islets were reduced slightly, but this was not significant enough to explain the reduced levels of the blood insulin. The secretion of insulin from isolated islets in response to glucose or depolarizing stimulation was impaired. These results suggest that the a3 isoform of V-ATPase has a regulatory function in the exocytosis of insulin secretion.

Key words: V-ATPase, Insulin secretion, Exocytosis, a3 isoform, Mouse mutant

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