Cloning and Characterization of a Novel Mammalian Zinc Transporter, Zinc Transporter 5, Abundantly Expressed in Pancreatic β Cells

Kambe, Taiho; Narita, Hiroshi; Yamaguchi-Iwai, Yuko; Hirose, Junko; Amano, Tatsuaki; Sugiura, Naomi; Sasaki, Ryuzo; Mori, Koshi; Iwanaga, Toshihiko; Nagao, Masaya

doi:10.1074/jbc.m200910200

Cited by 232 publications

(247 citation statements)

References 36 publications

(36 reference statements)

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“…On the other hand, we estimate that most of the zinquin fluorescence detected by us is due to ZnT3 because ZnT3 Ϫ/Ϫ mice completely lack ionic zinc in their hippocampus (Cole et al, 1999). However, the contribution of other zinc transporters expressed in brain, although likely to be minor (Huang, 1997;Huang et al, 2002;Kambe et al, 2002), cannot be ruled out yet. Nonetheless, our confocal microscopy immuno-localization studies in hippocampal neurons and the biochemical analysis of brain SV from wild-type and AP-3-deficient mocha brains support the hypothesis that vesicles possess variable stoichiometry of their constituents.…”

Section: Discussionmentioning

confidence: 76%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

109

178

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Synaptic vesicles (SV) are generated by two different mechanisms, one AP-2 dependent and one AP-3 dependent. It has been uncertain, however, whether these mechanisms generate SV that differ in molecular composition. We explored this hypothesis by analyzing the targeting of ZnT3 and synaptophysin both to PC12 synaptic-like microvesicles (SLMV) as well as SV isolated from wild-type and AP-3-deficient mocha brains. ZnT3 cytosolic tail interacted selectively with AP-3 in cell-free assays. Accordingly, pharmacological disruption of either AP-2-or AP-3-dependent SLMV biogenesis preferentially reduced synaptophysin or ZnT3 targeting, respectively; suggesting that these antigens were concentrated in different vesicles. As predicted, immuno-isolated SLMV revealed that ZnT3 and synaptophysin were enriched in different vesicle populations. Likewise, morphological and biochemical analyses in hippocampal neurons indicated that these two antigens were also present in distinct but overlapping domains. ZnT3 SV content was reduced in AP-3-deficient neurons, but synaptophysin was not altered in the AP-3 null background. Our evidence indicates that neuroendocrine cells assemble molecularly heterogeneous SV and suggests that this diversity could contribute to the functional variety of synapses. INTRODUCTIONThe molecular diversity in total brain synaptic vesicle (SV) composition is generally presumed to result from differential expression of synaptic vesicle membrane proteins in different brain regions. However, the possibility that synaptic vesicles differ in composition because of different biogenesis mechanisms has not been explored. Different vesiculation pathways could result in molecularly diverse synaptic vesicles. Vesiculation mechanisms are known to produce distinct cargo carriers from a population of donor membranes (Bonifacino and Dell'Angelica, 1999;Springer et al., 1999;Boehm and Bonifacino, 2001). This process is achieved by adaptor complexes that recognize and concentrate specific membrane proteins in the donor membranes (Bonifacino and Dell 'Angelica, 1999;Kirchhausen, 1999). PC12 cells have been shown to possess two such adaptor-dependent pathways for the assembly of synaptic vesicles, also known as synaptic-like microvesicles (SLMV) (Shi et al., 1998;de Wit et al., 1999;Jarousse and Kelly, 2001). In one pathway, SLMV are generated from the plasma membrane by a vesiculation mechanism that requires the adaptor AP-2, clathrin, and the GTPase dynamin (Shi et al., 1998). In the second pathway, SLMV are generated from endosomes by the adaptor complex AP-3 (Faundez et al., 1998;Blumstein et al., 2001) and the GTPase ARF1 (Faundez et al., 1997). In contrast to the plasma membrane pathway, the endosomederived mechanism is highly sensitive to brefeldin A (BFA) (Shi et al., 1998).Phenotypes observed in the AP-3-deficient mocha mouse are consistent with a role for the AP-3-dependent, endosome-derived pathway in neurons (Kantheti et al., 1998). The mocha mossy fibers are devoid of both the synaptic vesiclespecific zinc transpor...

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Section: Discussionmentioning

confidence: 76%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

109

178

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“…ZnT1, ubiquitously present in tissues, is the only member of the family localised at the plasma membrane, exporting zinc to the extracellular media [31]. ZnT5 and ZnT7 are also expressed [32,33]:…”

Section: Znt Familymentioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

140

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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“…ZnT proteins are members of the cation diffusion facilitator (CDF) family and function by either transporting zinc out of cells or by sequestering it into intracellular compartments, while ZIP proteins appear to be involved in the cellular uptake of zinc. The ZNT family of mammalian zinc transporters, of which there are now six members, share similar structures consisting of six transmembrane domains and a histidine-rich cytoplasmic loop, but differ from each other in their tissue specificity and intracellular location (McMahon and Cousins, 1998;Murgia et al, 1999;Huang et al, 2002;Kambe et al, 2002). ZNT1 is located at the plasma membrane and functions as a zinc efflux transporter (Palmiter and Findley, 1995), while ZNT2 and ZNT3 are thought to be involved in zinc sequestration in endosomal vesicles (Palmiter et al, 1996a, b).…”

Section: Discussionmentioning

confidence: 99%

Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer

et al. 2003

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Cloning and Characterization of a Novel Mammalian Zinc Transporter, Zinc Transporter 5, Abundantly Expressed in Pancreatic β Cells

Cited by 232 publications

References 36 publications

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Zinc and diabetes

Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer

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