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J. Biol. Chem., Vol. 281, Issue 14, 9361-9372, April 7, 2006

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The Zn²⁺-transporting Pathways in Pancreatic -Cells

A ROLE FOR THE L-TYPE VOLTAGE-GATED Ca²⁺ CHANNEL^*

Armen V. Gyulkhandanyan, Simon C. Lee, George Bikopoulos¹, Feihan Dai, and Michael B. Wheeler, Supported by a CIHR Investigator Award²

From the Departments of Physiology and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada

In pancreatic -cells Zn²⁺ is crucial for insulin biosynthesis and exocytosis. Despite this, little is known about mechanisms of Zn²⁺ transport into -cells or the regulation and compartmentalization of Zn²⁺ within this cell type. Evidence suggests that Zn²⁺ in part enters neurons and myocytes through specific voltage-gated calcium channels (VGCC). Using a Zn²⁺-selective fluorescent dye with high affinity and quantum yield, FluoZin-3 AM and the plasma membrane potential dye DiBAC₄(3) we applied fluorescent microscopy techniques for analysis of Zn²⁺-accumulating pathways in mouse islets, dispersed islet cells, and -cell lines (MIN6 and -TC6f7 cells). Because the stimulation of insulin secretion is associated with cell depolarization, Zn²⁺ (5-10 µM) uptake was analyzed under basal (1 mM glucose) and stimulatory (10-20 mM glucose, tolbutamide, tetraethylammonium, and high K⁺) conditions. Under both basal and depolarized states, -cells were capable of Zn²⁺ uptake, and switching from basal to depolarizing conditions resulted in a marked increase in the rate of Zn²⁺ accumulation. Importantly, L-type VGCC (L-VGCC) blockers (verapamil, nitrendipine, and nifedipine) as well as nonspecific inhibitors of Ca²⁺ channels, Gd³⁺ and La³⁺, inhibited Zn²⁺ uptake in -cells under stimulatory conditions with little or no change in Zn²⁺ accumulation under low glucose conditions. To determine the mechanism of VGCC-independent Zn²⁺ uptake the expression of a number of ZIP family Zn²⁺ transporter mRNAs in islets and -cells was investigated. In conclusion, we demonstrate for the first time that, in part, Zn²⁺ transport into -cells takes place through the L-VGCC. Our investigation demonstrates direct Zn²⁺ accumulation in insulin-secreting cells by two pathways and suggests that the rate of Zn²⁺ transport across the plasma membrane is dependent upon the metabolic status of the cell.

Received for publication, August 3, 2005 , and in revised form, December 19, 2005.

^* This work was supported in part by an operating grant (MOP-49521) from the Canadian Institutes of Health Research (CIHR) (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 data.

¹ Supported by a Banting and Best Diabetes Center (BBDC) Studentship.

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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