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J. Biol. Chem., Vol. 283, Issue 15, 10184-10197, April 11, 2008

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Investigation of Transport Mechanisms and Regulation of Intracellular Zn²⁺ in Pancreatic -Cells^*

Armen V. Gyulkhandanyan, Hongfang Lu, Simon C. Lee, Alpana Bhattacharjee, Nadeeja Wijesekara¹, Jocelyn E. Manning Fox, Patrick E. MacDonald, Fabrice Chimienti^¶, Feihan F. Dai, and Michael B. Wheeler²

From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, the Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada, and ^¶Mellitech, DRMFC/SC1B, CEA Grenoble, 38054 Grenoble, France

During insulin secretion, pancreatic -cells are exposed to Zn²⁺ released from insulin-containing secretory granules. Although maintenance of Zn²⁺ homeostasis is critical for cell survival and glucagon secretion, very little is known about Zn²⁺-transporting pathways and the regulation of Zn²⁺ in -cells. To examine the effect of Zn²⁺ on glucagon secretion and possible mechanisms controlling the intracellular Zn²⁺ level ([Zn²⁺]_i), we employed a glucagon-producing cell line (-TC6) and mouse islets where non-β-cells were identified using islets expressing green fluorescent protein exclusively in β-cells. In this study, we first confirmed that Zn²⁺ treatment resulted in the inhibition of glucagon secretion in -TC6 cells and mouse islets in vitro. The inhibition of secretion was not likely via activation of K_ATP channels by Zn²⁺. We then determined that Zn²⁺ was transported into -cells and was able to accumulate under both low and high glucose conditions, as well as upon depolarization of cells with KCl. The nonselective Ca²⁺ channel blocker Gd³⁺ partially inhibited Zn²⁺ influx in -TC cells, whereas the L-type voltage-gated Ca²⁺ channel inhibitor nitrendipine failed to block Zn²⁺ accumulation. To investigate Zn²⁺ transport further, we profiled -cells for Zn²⁺ transporter transcripts from the two families that work in opposite directions, SLC39 (ZIP, Zrt/Irt-like protein) and SLC30 (ZnT, Zn²⁺ 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 [Zn²⁺]_i, we examined the effects of oxidizing agents on Zn²⁺ mobilization within -cells. 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. Zn²⁺ transporters and the redox state also modulate [Zn²⁺]_i.

Received for publication, August 21, 2007 , and in revised form, January 31, 2008.

^* This work was supported by Canadian Institutes of Health Research Operating Grant MOP-49521 (to M. B. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1 and 2.

¹ Supported by a studentship from Canadian Institute of Health Research.

² To whom correspondence should be addressed: Dept. of Physiology, University of Toronto, 1 King's College Circle, Rm. 3352, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.

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