Abstract
During insulin secretion, pancreatic alpha-cells are exposed to Zn(2+) released from insulin-containing secretory granules. Although maintenance of Zn(2+) homeostasis is critical for cell survival and glucagon secretion, very little is known about Zn(2+)-transporting pathways and the regulation of Zn(2+) in alpha-cells. To examine the effect of Zn(2+) on glucagon secretion and possible mechanisms controlling the intracellular Zn(2+) level ([Zn(2+)](i)), we employed a glucagon-producing cell line (alpha-TC6) and mouse islets where non-beta-cells were identified using islets expressing green fluorescent protein exclusively in beta-cells. In this study, we first confirmed that Zn(2+) treatment resulted in the inhibition of glucagon secretion in alpha-TC6 cells and mouse islets in vitro. The inhibition of secretion was not likely via activation of K(ATP) channels by Zn(2+). We then determined that Zn(2+) was transported into alpha-cells and was able to accumulate under both low and high glucose conditions, as well as upon depolarization of cells with KCl. The nonselective Ca(2+) channel blocker Gd(3+) partially inhibited Zn(2+) influx in alpha-TC cells, whereas the L-type voltage-gated Ca(2+) channel inhibitor nitrendipine failed to block Zn(2+) accumulation. To investigate Zn(2+) transport further, we profiled alpha-cells for Zn(2+) transporter transcripts from the two families that work in opposite directions, SLC39 (ZIP, Zrt/Irt-like protein) and SLC30 (ZnT, Zn(2+) transporter). We observed that Zip1, Zip10, and Zip14 were the most abundantly expressed Zips and ZnT4, ZnT5, and ZnT8 the dominant ZnTs. Because the redox state of cells is also a major regulator of [Zn(2+)](i), we examined the effects of oxidizing agents on Zn(2+) mobilization within alpha-cells. 2,2'-Dithiodipyridine (-SH group oxidant), menadione (superoxide generator), and SIN-1 (3-morpholinosydnonimine) (peroxynitrite generator) all increased [Zn(2+)](i) in alpha-cells. Together these results demonstrate that Zn(2+) inhibits glucagon secretion, and it is transported into alpha-cells in part through Ca(2+) channels. Zn(2+) transporters and the redox state also modulate [Zn(2+)](i).
Highlights
␣-TC6 cells and mouse islets in vitro
The mechanisms that control the suppression of glucagon secretion under high glucose conditions have not been completely agreed upon, but it is likely that ␣-cells sense and respond to changes in blood glucose through direct and indirect mechanisms [3,4,5,6]
Some of the paracrine/endocrine factors that could facilitate the suppression of glucagon secretion include insulin and other factors released upon -cell exocytosis, including ␥-aminobutyric acid and Zn2ϩ [3, 7, 8]
Summary
␣-TC6 cells and mouse islets in vitro. The inhibition of secretion was not likely via activation of KATP channels by Zn2؉. 2,2-Dithiodipyridine (؊SH group oxidant), menadione (superoxide generator), and SIN-1 (3-morpholinosydnonimine) (peroxynitrite generator) all increased [Zn2؉]i in ␣-cells Together these results demonstrate that Zn2؉ inhibits glucagon secretion, and it is transported into ␣-cells in part through Ca2؉ channels. Following exocytosis of the intracellular vesicles, it is likely that the Zn2ϩ released into the extracellular islet space would be transported back into the host cell or into neighboring cells. It was found that switching off pancreatic artery infusions of Zn2ϩ stimulated glucagon secretion in rats [14]. Contrary to these experiments, a lack of Zn2ϩ effect on glucagon secretion was observed in mouse islets [15]. The efflux of Zn2ϩ or intracellular Zn2ϩ sequestration is promoted by CDF/
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