The Zn2+-transporting Pathways in Pancreatic β-Cells

In pancreatic β-cells Zn2+ is crucial for insulin biosynthesis and exocytosis. Despite this, little is known about mechanisms of Zn2+ transport into β-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 β-cell lines (MIN6 and β-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, β-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 β-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 β-cells was investigated. In conclusion, we demonstrate for the first time that, in part, Zn2+ transport into β-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. In pancreatic β-cells Zn2+ is crucial for insulin biosynthesis and exocytosis. Despite this, little is known about mechanisms of Zn2+ transport into β-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 β-cell lines (MIN6 and β-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, β-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 β-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 β-cells was investigated. In conclusion, we demonstrate for the first time that, in part, Zn2+ transport into β-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. Zinc is an important trace element in living organisms, and it plays a key role in many biological processes (1Prasad A.S. Nutrition. 1995; 11: 93-99PubMed Google Scholar, 2Berg J.M. Shi Y.G. Science. 1996; 271: 1081-1085Crossref PubMed Scopus (1687) Google Scholar). Under normal conditions the concentration of free Zn2+ in cells is extremely low (3Emdin S.O. Dodson G.G. Cutfield J.M. Cutfield S.M. Diabetologia. 1980; 19: 174-182Crossref PubMed Scopus (228) Google Scholar). However, the total intracellular Zn2+ concentration can reach 150-200 μm (4Outten C.E. O'Halloran T.V. Science. 2001; 292: 2488-2492Crossref PubMed Scopus (1173) Google Scholar, 5Palmiter R.D. Findley S.D. EMBO J. 1995; 14: 639-649Crossref PubMed Scopus (643) Google Scholar). A low concentration of Zn2+ in the cytoplasm is maintained by Zn2+-buffering systems such as metallothioneins and by compartmentalization into intracellular vesicles (6Hamer D.H. Ann. Rev. Biochem. 1986; 55: 913-951Crossref PubMed Google Scholar, 7Gaither L.A. Eide D.J. Biometals. 2001; 14: 251-270Crossref PubMed Scopus (433) Google Scholar). Regulation of Zn2+ metabolism in cells can also include plasma membrane Zn2+ transporters that can have opposite roles in cellular Zn2+ homeostasis. The Zip (Zrt/Irt-related protein) family of metal ion transporters facilitates Zn2+ uptake from the extracellular space or the lumen of intracellular organelles into the cytoplasm, whereas the ZnT (zinc transporter) family of transporters promotes Zn2+ efflux from cells or into various intracellular compartments (8Liuzzi J.P. Cousins R.J. Ann. Rev. Nutr. 2004; 24: 151-172Crossref PubMed Scopus (473) Google Scholar, 9Palmiter R.D. Huang L.P. Pflugers Arch. Eur. J. Physiol. 2004; 447: 744-751Crossref PubMed Scopus (335) Google Scholar, 10Eide D.J. Pflugers Arch. Eur. J. Physiol. 2004; 447: 796-800Crossref PubMed Scopus (304) Google Scholar). In pancreatic β-cells a fraction of the intracellular Zn2+ pool is stored with insulin in vesicles as a complex of Zn2+-insulin with a stoichiometry of 2:1 (3Emdin S.O. Dodson G.G. Cutfield J.M. Cutfield S.M. Diabetologia. 1980; 19: 174-182Crossref PubMed Scopus (228) Google Scholar). During exocytosis Zn2+ is released together with insulin into the extracellular medium. The concentration of Zn2+ in insulin-containing vesicles of β-cells is ∼20 mm (11Foster M.C. Leapman R.D. Li M.X. Atwater I. Biophys. J. 1993; 64: 525-532Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Hutton J.C. Penn E.J. Peshavaria M. Biochem. J. 1983; 210: 297-305Crossref PubMed Scopus (168) Google Scholar). Thus during exocytosis Zn2+ is released from vesicles into the extracellular space and, because of the increase of Zn2+, it can be transported back into the host cell or into neighboring cells (13Franklin I. Gromada J. Gjinovci A. Theander S. Wollheim C.B. Diabetes. 2005; 54: 1808-1815Crossref PubMed Scopus (247) Google Scholar). Although there is a significant amount of literature regarding transport of Zn2+ into various types of cells (14Gaither L.A. Eide D.J. J. Biol. Chem. 2001; 276: 22258-22264Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 15Colvin R.A. Neurosci. Lett. 1998; 247: 147-150Crossref PubMed Scopus (37) Google Scholar, 16Reyes J.G. Am. J. Physiol. 1996; 39: C401-C410Crossref Google Scholar, 17Wang F.D. Kim B.E. Petris M.J. Eide D.J. J. Biol. Chem. 2004; 279: 51433-51441Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 18Sensi S.L. Yin H.Z. Weiss J.H. Eur. J. Neurosci. 2000; 12: 3813-3818Crossref PubMed Scopus (137) Google Scholar, 19Sensi S.L. Canzoniero L.M.T. Yu S.P. Ying H.S. Koh J.Y. Kerchner G.A. Choi D.W. J. Neurosci. PubMed Google Scholar, J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. I. Biochem. Biophys. 2004; PubMed Scopus Google Scholar, A. S.L. Weiss J.H. M. I. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. Yin H.Z. Weiss J.H. S. A. PubMed Scopus Google Scholar, A. Biochem. J. PubMed Scopus Google little is known about transport of Zn2+ into the of mechanisms of Zn2+ uptake into pancreatic islets under basal and stimulatory conditions and that Zn2+ be for metabolic processes in to insulin M. Diabetes. PubMed Scopus Google Scholar, Diabetes. 1980; PubMed Scopus Google Scholar). The and of Zn2+ in islets is also under in cells have of Zn2+ S. Diabetologia. PubMed Scopus Google Scholar, S. Diabetologia. PubMed Scopus Google whereas with of islets have that of the total islet Zn2+ was associated with the fraction Diabetes. 1980; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). the of Zn2+ for biosynthesis and the mechanisms of uptake into islet cells is of the Zn2+ transport in and to β-cell associated with J. Am. Nutr. 1998; PubMed Scopus Google Scholar). is also known that Zn2+ can J. 2000; PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar, T.V. 2005; PubMed Scopus Google depolarization, of the S.L. Weiss J.H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. J.M. 2004; PubMed Scopus Google and as a of J. Biometals. 2001; 14: PubMed Scopus Google Scholar). In it that Zn2+ can as a in pancreatic cell Kim Kim S. Kim Koh J.Y. Kim Diabetes. 2000; PubMed Scopus Google and in the of secretion from (13Franklin I. Gromada J. Gjinovci A. Theander S. Wollheim C.B. Diabetes. 2005; 54: 1808-1815Crossref PubMed Scopus (247) Google Scholar, Gjinovci A. Wollheim C.B. Biol. PubMed Scopus Google Scholar). of pancreatic β-cells that the of insulin secretion J.C. Pflugers Arch. Eur. J. Physiol. 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Neurosci. 2000; 12: 3813-3818Crossref PubMed Scopus (137) Google Scholar, 19Sensi S.L. Canzoniero L.M.T. Yu S.P. Ying H.S. Koh J.Y. Kerchner G.A. Choi D.W. J. Neurosci. PubMed Google Scholar). the transport of Zn2+ into cells is by J.G. Am. J. Physiol. 1996; 39: C401-C410Crossref Google Scholar, 17Wang F.D. Kim B.E. Petris M.J. Eide D.J. J. Biol. Chem. 2004; 279: 51433-51441Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, M. Diabetes. PubMed Scopus Google Scholar, Diabetes. 1980; PubMed Scopus Google Ca2+ fluorescent J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. I. Biochem. Biophys. 2004; PubMed Scopus Google Scholar, 2004; PubMed Scopus Google or the fluorescent dye A. S.L. Weiss J.H. M. I. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. Yin H.Z. Weiss J.H. S. A. PubMed Scopus Google Scholar, A. Biochem. J. PubMed Scopus Google Scholar). a Zn2+-selective fluorescent was as a for Zn2+ S.L. Weiss J.H. PubMed Scopus Google Scholar). FluoZin-3 Zn2+ with high affinity and it quantum S.L. Weiss J.H. PubMed Scopus Google Scholar). a of the FluoZin-3 to the pathways in the β-cell lines and β-TC6f7 mouse islets, and dispersed islet that Zn2+ uptake into β-cells through two the plasma membrane Zn2+ transporter under basal conditions and through during the of the plasma Our that Zn2+ into β-cells is to the metabolic status of the cell. Under stimulatory Zn2+ is through the L-type whereas under basal conditions uptake is of this and dependent the ZIP family of To this we demonstrate by time analysis the expression of and in cells and mouse islets, with and the in cells and in FluoZin-3 were from was from nitrendipine, tolbutamide, La3+, and were from and cells a from S. were in high glucose with and cells a from S. were in with mm glucose, mm in both cell lines was and cells were in to fluorescent cell were by The cells were and the was in and with cells were maintained in for with cells were were from as M. Diabetes. PubMed Scopus Google Scholar, S. Kim C.B. 2001; Full Text Full Text PDF PubMed Scopus Google with were and the pancreatic was with and The was and for were by to and maintained The islets were in with mm glucose, mm The islets were with or and maintained in for dispersed cells, islets were for in with mm mm glucose, and were and with for for by the of with mm glucose, and mm The was and the in the medium. The cells were with and maintained in for fluorescent the and the mm mm mm mm mm mm or the In to the cells, mm was with mm were an fluorescent with and with a high from was the of the and as well as for fluorescent and of the was the cells or islets were to an the and were In a was for cells or islets were analyzed of Zn2+ and Zn2+ with dispersed islet cells, or islets were with μm FluoZin-3 AM for in in the of low glucose (1 and The cells or islets were for in the conditions The of FluoZin-3 AM was and with the of dispersed islet cells, with FluoZin-3 AM and to with Zn2+ in for the were of and the was of However, of cells with the Zn2+ in the of Zn2+ to a increase of to the of Zn2+ To this increase in Zn2+ was in the In this with in the of Zn2+ to a increase of that with Zn2+ resulted in a significant increase of was the dye with cells or islets were with dye for the conditions as with FluoZin-3 The the concentration of The was and was a and Although for FluoZin-3 and DiBAC4(3) were we to and to the the was for was a with islets, dispersed cells, or cells with FluoZin-3 AM or with FluoZin-3 AM and were into the and the of the with a both FluoZin-3 AM and the was and were and of The was by the the with were to by the the The were analyzed with cells with FluoZin-3 AM μm) and the (1 μm) were into the and the of the with a and FluoZin-3 AM and and of were The was for for Zinc was from cells, mouse islets, and mouse to the total was with and first of was and to the The or was for in of mouse were for the of a and and a or was to a the of of of mm of μm of and of of mm of of in and of the was of was in an were the in The expression of various Zip was the 1993; 11: PubMed Scopus Google Scholar). were to mouse and the of were in or cell or islets, and The were The of and dispersed islet cell as from cells as of with was as the of during the of the In the of islets the from islet and from two from and the of islet In in the the cells were from the and islets were from the Zn2+ and a of the dye FluoZin-3 was to efflux of Zn2+ from the cells Chem. PubMed Scopus Google Scholar). In the we the FluoZin-3 AM to the intracellular and of Zn2+ accumulation into β-cell lines and and fluorescent of a cell with μm FluoZin-3 The in a of in with low glucose and in the of of μm Zn2+ to cells the with the tolbutamide, an of the a increase of was The of the in under the and of demonstrate a of the fluorescent from the of the cells with Zn2+ and with the was and the of was to a in the cell. were with cell in to the part of the cell that Zn2+ into the with of cells with FluoZin-3 AM and the the of Zn2+ within the A of of dispersed mouse islet cells with Zn2+ for under depolarized conditions mm also Zn2+ accumulation in the the increase in Zn2+ and and and the accumulation of Zn2+ in the space the is that a of of cells with FluoZin-3 AM and the membrane potential a of with of because of the of Zn2+ within is to the of in the into the of Zn2+ to in S.L. Weiss J.H. S. A. PubMed Scopus Google Scholar, M.C. J. Biochem. PubMed Scopus Google Scholar, A. J.H. G.A. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2005; PubMed Scopus Google the and increase in Zn2+ into the a was FluoZin-3 AM and μm the in Zn2+ and in cells basal and depolarizing conditions. A in demonstrates the of cells with mm glucose by μm tolbutamide, mm and a Zn2+ from this of cells with μm mm glucose to a increase of basal accumulation of with and with resulted in a increase of Zn2+ was to the of μm The in a of and fluorescent from the the in the of the of the FluoZin-3 in A. The of the rate of Zn2+ a significant of both and Zn2+ In of cells in the to Zn2+ To determine that the conditions in to cell we with the dye for in in the of mm glucose, cells in a of with and depolarized the plasma membrane of because of the of the fluorescent of the cells To determine Zn2+ accumulation and be in mouse islets, were with FluoZin-3 and for to and A in demonstrates of Zn2+ accumulation in an islet during with the as in The the of the islet and from and as in the and fluorescent of the islet of The of the in that the rate of Zn2+ accumulation during the of is fluorescent and of DiBAC4(3) of an islet with depolarizing were from the islet and from and from the of is in the of the is known that the cell types in islets β-cells and and Gjinovci A. Wollheim C.B. Biol. PubMed Scopus Google Scholar, A. Science. PubMed Scopus Google and in mouse islets the of a β-cell M. M.J. A. J. 2005; PubMed Scopus Google Scholar). To determine the of in the of the islet we a A of through the islet and in the of the also of the cells β-cells M. M.J. A. J. 2005; PubMed Scopus Google Scholar). The of the islet a of the dye to the of the also with dispersed islet cells Because we the FluoZin-3 from the cells of β-cells is the Diabetes. 2004; PubMed Scopus Google Scholar, Gromada J. S. A. J. 2005; 19: PubMed Scopus Google it is that of demonstrates that the of Zn2+ accumulation in dispersed cells to in (MIN6 and is known that high affinity for Zn2+ G.A. J.P. J.C. J. Biol. Chem. 1983; Full Text PDF PubMed Google affinity for Ca2+ or M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). that the in FluoZin-3 Zn2+ accumulation into cells, an increase in intracellular Ca2+ to Ca2+ or a of Zn2+ intracellular Ca2+ To this we the in of FluoZin-3 cells in the of Our that of cells with mm glucose by mm glucose, mm and by μm Zn2+ in an increase of with islets and dispersed islet cells also the of a Ca2+ the Zn2+ dye and from with high glucose in the of Zn2+ in the resulted in a in intracellular Zn2+ was associated with insulin in islets with that Zn2+ can in the of insulin secretion Diabetes. PubMed Scopus Google Scholar). in were in of Ca2+ and To determine Ca2+ Zn2+ we Zn2+ transport in conditions with with cells significant of Zn2+ transport conditions demonstrate that Zn2+ can transport across the plasma membrane in and islet cells under basal and conditions. Zn2+ have that Zn2+ can in β-cells under low glucose (1 mm glucose) and cell depolarization, or the rate of Zn2+ transport into the The of a glucose FluoZin-3 cells and islets, is in of cells with high glucose to significant Zn2+ accumulation with DiBAC4(3) that with mm glucose to the of the plasma membrane of islets with a stimulatory amount of glucose also resulted in Zn2+ accumulation with mm glucose to of the plasma membrane in islets as well The of Zn2+ is well known that insulin secretion the of the of Diabetologia. PubMed Scopus Google Scholar). that with mm glucose a increase in the rate of Zn2+ accumulation with high glucose both in cells and islets with DiBAC4(3) the in in cells and in islets of L-type Ca2+ Zn2+ is known that L-type channels a and by and Rev. PubMed Google Scholar). of the role of in Zn2+ transport we nitrendipine, and as well as the nonspecific inhibitors of Ca2+ and In is a trace of the from with the of with μm Zn2+ from Zn2+ uptake under conditions (1 mm However, it Zn2+ accumulation. known also Zn2+ uptake in and cells and demonstrates the of the nonspecific Ca2+ Gd3+ the of Zn2+ during the of cells with a stimulatory amount of the from from with μm Gd3+ the increase in Zn2+ accumulation by mm L-type or the nonspecific Ca2+ also Zn2+ accumulation. with islets that Zn2+ accumulation under basal conditions inhibited Zn2+ accumulation by as in cells that Zn2+ transport is by Zn2+ through the L-VGCC. of Zinc in and to the mechanism of Zn2+ we to for Zn2+ transporter expression in cells and Our analysis that for and in cells as well as pancreatic islets as in were from the of the as well as the for that and the transporter in cells, by and transporter were in cells to a In islets the transporters were and that Zn2+ is an important element in R.A. M. Eur. J. PubMed Scopus Google Scholar, Koh J.Y. Rev. Neurosci. 2005; PubMed Scopus Google Scholar). this we as a for the expression of various Zip Our in that the Zn2+ transporter in were and The high expression of in the (14Gaither L.A. Eide D.J. J. Biol. Chem. 2001; 276: 22258-22264Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). In the β-cell Zn2+ an important role in the of insulin and as a for many is also that Zn2+ can Ca2+ in cells and insulin secretion in an is by the that Zn2+ can Ca2+ and channels, as in and cell lines as well as M. A. I. Biochem. Biophys. 2004; PubMed Scopus Google Scholar, I. A. J. 2004; PubMed Scopus Google Scholar). The mechanism of Zn2+ transport into β-cells through the plasma membrane that a mechanism of Zn2+ low Zn2+ μm) and a mechanism Zn2+ μm) M. Diabetes. PubMed Scopus Google Scholar). 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Diabetes. 2004; PubMed Scopus Google Scholar). in that with stimulatory of glucose Zn2+ into The rate of Zn2+ accumulation is with of and channels the plasma of an cell in and the of FluoZin-3 and DiBAC4(3) in cells islets and dispersed islet cells also that Zn2+ accumulation takes place of cells by the or by with specific inhibitors of (verapamil, nitrendipine, and nifedipine) that of the pathways of Zn2+ into β-cells is the L-type The in and that low glucose Zn2+ can in both cells and mouse Importantly, Ca2+ blockers and this whereas Zn2+ is by A of is that Zn2+ can into β-cells also transport membrane Zn2+ in types of cells (8Liuzzi J.P. Cousins R.J. Ann. Rev. Nutr. 2004; 24: 151-172Crossref PubMed Scopus (473) Google Scholar, 9Palmiter R.D. Huang L.P. Pflugers Arch. Eur. J. Physiol. 2004; 447: 744-751Crossref PubMed Scopus (335) Google Scholar, 10Eide D.J. Pflugers Arch. Eur. J. 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Chem. 2004; 279: 51433-51441Abstract Full Text Full Text PDF PubMed Scopus (126) Google the expression was in the J. J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Using the of in pancreatic β-cells was also J. J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Our time for of of the ZIP family of Zn2+ transporters in cells and islets that with various of include and with and the of expression in cells, and with and in islets of with J. F.D. Eide J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google regarding the expression of mouse is by the that islets a fraction of the total of the also with of in islets in cells The for such a of transporters in β-cells is The mechanism of of as well as of plays a role in Zn2+ uptake in basal conditions is that accumulation of Zn2+ through this is by in plasma membrane to the specific of transporters and regulation of is and to the of and cells during is an of transporter regulation J. J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). also that in cells, and transporters can the plasma membrane and intracellular compartments F.D. J. Kim B.E. Petris M.J. Eide D.J. J. Biol. 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