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Showing SLC30A1 — ZNT1 is a alias.

SLC30A1

Proton-coupled zinc antiporter SLC30A1 · UniProt Q9Y6M5

Length
507 aa
Mass
55.3 kDa
Annotated
2026-06-10
71 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC30A1/ZnT1 is the principal plasma membrane zinc efflux transporter that protects cells from zinc toxicity and, at the organismal level, governs systemic zinc homeostasis through its basolateral localization in enterocytes (PMID:24951051, PMID:39422023, PMID:9560190). It functions as a Zn2+/H+ exchanger whose efflux activity depends on conserved zinc-binding residues, with His43 critical for zinc selectivity defined by cryo-EM structure; intestinal-specific deletion impairs survival, establishing this transport role as essential in vivo (PMID:24951051, PMID:39422023). Its soluble C-terminal domain forms a dimer and the antiporter mechanism has been reconstituted from purified protein (PMID:33996761). ZnT1 expression is controlled at the transcriptional level by zinc/cadmium-activated MTF-1 binding metal-response elements in its promoter, and post-translationally by zinc-dependent endocytosis and proteasomal/lysosomal degradation, coupling its abundance to cellular zinc status (PMID:10952993, PMID:31471319, PMID:26824222). Beyond ion transport, ZnT1 carries out transport-independent signaling functions through its intracellular C-terminal domain: it inhibits L-type calcium channels and activates Raf-1/ERK signaling to augment T-type calcium channel surface expression, with these activities mapping to the C-terminus rather than the membrane-spanning transport segments (PMID:28091657, PMID:22193398, PMID:22572848). At synapses, ZnT1 physically associates with the GluN2A NMDAR subunit to mediate tonic zinc inhibition of NMDAR currents (PMID:32937457, PMID:36202195). In macrophages, ZnT1 controls endosomal and vesicular zinc to drive antimicrobial zinc toxicity, NO-mediated killing, and endocytosis of TLR4 and PD-L1 (PMID:32441444, PMID:39475776, PMID:37816045). Somatic in-frame deletions near the zinc-binding site cause primary aldosteronism by inducing pathological Na+ influx and downstream Ca2+-driven CYP11B2/aldosterone production (PMID:37709865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1998 Medium

    Establishing where ZnT1 acts in the body, intestinal ZnT1 was localized to the basolateral enterocyte surface and shown to be regulated by dietary zinc, framing it as a vectorial zinc-export transporter at the absorptive epithelium.

    Evidence Immunofluorescence and Western blot with dietary zinc manipulation in rats

    PMID:9560190

    Open questions at the time
    • Transport mechanism not yet defined
    • No causal genetic test of intestinal requirement
  2. 2000 High

    To explain how zinc induces its own export machinery, MTF-1 was shown to bind metal-response elements in the ZnT1 promoter and to be required for basal and metal-induced ZnT1 expression, linking zinc sensing to transporter gene regulation.

    Evidence In vitro DNA-binding, MTF-1 knockout MEFs and knockout mice, in situ hybridization

    PMID:10952993

    Open questions at the time
    • Does not address post-transcriptional regulation
    • Tissue specificity of induction not fully resolved
  3. 2000 Medium

    Demonstrating the cytoprotective payoff of zinc export, ZnT1 overexpression enhanced Zn2+ efflux and reduced zinc-induced death while dominant-negative ZnT1 did the opposite, establishing ZnT1 as a determinant of zinc toxicity resistance.

    Evidence Stable overexpression and dominant-negative expression in PC12 cells, efflux and cell death assays

    PMID:11119691

    Open questions at the time
    • Transport mechanism (ion coupling) not determined
    • Endogenous-level evidence lacking
  4. 2004 Medium

    Two studies probed how ZnT1 lowers intracellular zinc, one showing it reduces zinc influx through L-type channels rather than only accelerating efflux, and another confirming sufficiency to confer zinc protection in astrocytes, broadening its role to influx regulation across cell types.

    Evidence Fluorescent zinc transport in HEK293/PC-12 cells with LTCC co-expression; heterologous ZnT1 expression in primary astrocytes

    PMID:15378655 PMID:15451416

    Open questions at the time
    • Single primary method (fluorescence) in each
    • Molecular basis of channel modulation unresolved
  5. 2006 High

    Loss- and gain-of-function across neurons and cardiomyocytes established ZnT1 as a physiological regulator of cation permeation through L-type Ca2+ channels, with in vivo atrial pacing linking ZnT1 induction to channel inhibition.

    Evidence siRNA in cortical neurons; overexpression/knockdown in cardiomyocytes, Xenopus oocyte electrophysiology, in vivo rat atrial pacing

    PMID:16741752 PMID:17196651

    Open questions at the time
    • Whether channel regulation requires zinc transport not yet separated
    • Direct ZnT1-channel interaction not mapped
  6. 2008 Medium

    Direct loss-of-function in neurons confirmed ZnT1's intrinsic efflux role, as shRNA knockdown decreased Zn2+ efflux with kinetics dependent on the intracellular zinc gradient.

    Evidence Vector-based shRNA knockdown in primary cortical neurons, FluoZin-3 microfluorometry

    PMID:19095042

    Open questions at the time
    • Only ~40% knockdown limits interpretation
    • Ion-coupling mechanism not addressed
  7. 2009 High

    Cross-species rescue established functional conservation: Drosophila gut ZnT1 is essential for dietary zinc absorption and human ZnT1 (but not ZnT4/ZnT7) rescued the defect, confirming a conserved, specific basolateral export function.

    Evidence RNAi in Drosophila with human ZnT1/ZnT4/ZnT7 rescue, immunofluorescence, zinc tolerance assays

    PMID:19325039

    Open questions at the time
    • Mammalian in vivo intestinal requirement not yet tested
    • Transport mechanism not addressed
  8. 2011 High

    The C-terminal domain was shown to be a signaling module: it activates Raf-1/ERK to protect cardiomyocytes from ischemia-reperfusion injury, with the CTD alone sufficient, revealing a function distinct from zinc transport.

    Evidence Truncation constructs in HL-1 cardiomyocytes, phospho-ERK immunoblot, MEK inhibitor, cell death assays

    PMID:22193398

    Open questions at the time
    • Direct Raf-1 binding not shown here
    • How ERK activation is initiated by the CTD unresolved
  9. 2012 High

    Extending the signaling role, ZnT1 was shown to augment T-type Ca2+ channel surface expression via Ras-ERK signaling, with dominant-negative Raf-1 and MEK inhibition blocking the effect, defining a transport-independent channel-trafficking function.

    Evidence Xenopus oocyte/CHO electrophysiology, surface biotinylation, TIRF microscopy, dominant-negative Raf-1, MEK inhibitor

    PMID:22572848

    Open questions at the time
    • Physiological context of T-type augmentation untested in vivo
    • Mechanism of ERK engagement still indirect
  10. 2013 High

    A triple-knockout rescue experiment showed ZnT1's zinc transport activity specifically supports activation of secretory-pathway zinc enzymes (TNAP), as only transport-competent ZnT1 restored activity, distinguishing its catalytic from signaling roles.

    Evidence ZnT1/MT/ZnT4 triple-KO cells, re-expression of WT vs transport-deficient mutants, TNAP activity assay

    PMID:24204829

    Open questions at the time
    • Mechanism of zinc delivery to the secretory pathway not resolved
    • Generalizability to other zinc enzymes untested
  11. 2016 Medium

    MTF1 was confirmed as the specific transcriptional controller of ZnT1 and metallothionein among the broader zinc transcriptome, sharpening the regulatory logic of zinc buffering.

    Evidence siRNA MTF1 knockdown in Caco-2 cells, transcriptome analysis

    PMID:26824222

    Open questions at the time
    • Direct promoter occupancy not re-demonstrated here
    • Post-transcriptional layer not addressed
  12. 2017 High

    Domain dissection definitively separated ZnT1's two activities, showing zinc transport-abolishing mutations leave L-type channel inhibition intact and the CTD alone inhibits the channel, establishing dual, structurally independent functions.

    Evidence Site-directed mutagenesis, truncation constructs, electrophysiology in Xenopus oocytes and mammalian cells

    PMID:28091657

    Open questions at the time
    • Direct CTD-channel interaction surface not mapped
    • Stoichiometry of inhibition unknown
  13. 2019 High

    Two studies defined post-translational control: zinc-dependent endocytosis/degradation and N-glycosylation tune ZnT1 stability and surface abundance, and cancer-derived missense mutations were validated as loss-of-function, linking sequence to transport.

    Evidence Subcellular fractionation, proteasome/lysosome inhibitors, Asn299 mutagenesis; functional zinc transport assays of COSMIC/gnomAD variants

    PMID:31471319 PMID:31728210

    Open questions at the time
    • E3 ligase / trafficking machinery for endocytosis unidentified
    • Physiological consequences of cancer variants untested in vivo
  14. 2020 High

    A postsynaptic ZnT1-GluN2A association was shown to mediate tonic zinc inhibition of NMDARs, with peptide disruption abolishing inhibition, revealing a transporter-based synaptic zinc microdomain mechanism.

    Evidence Cell-permeant peptide disruption, electrophysiology in mouse dorsal cochlear nucleus slices, intracellular zinc manipulation

    PMID:32937457

    Open questions at the time
    • Direct binding interface of ZnT1-GluN2A not mapped
    • Whether transport activity is required not separated from interaction
  15. 2020 Medium

    In macrophages, LPS-induced SLC30A1 was shown to drive zinc-containing vesicle formation and intracellular zinc toxicity against bacteria, extending ZnT1's role to innate antimicrobial defense.

    Evidence LPS stimulation and ectopic overexpression in THP-1 cells, zinc vesicle and bacterial zinc-stress reporters, killing assays

    PMID:32441444

    Open questions at the time
    • Based on overexpression rather than endogenous loss of function
    • Vesicle compartment identity not defined
  16. 2021 High

    Studies in neurons and zebrafish broadened the picture: ZnT1 acts as a Zn2+/Ca2+ exchanger in cortical neurons, and Slc30a1 loss in zebrafish dysregulates a Snai2-Jag1b axis controlling neural crest differentiation, linking zinc export to development.

    Evidence AAV-shRNA knockdown with Zn2+/Ca2+ imaging and ion substitution in neurons; zebrafish morpholino knockdown, SMART-seq, epistasis rescue

    PMID:34871934 PMID:34977877

    Open questions at the time
    • Reconciliation of Zn2+/Ca2+ vs Zn2+/H+ coupling across cell types unresolved
    • Developmental axis tested only in ortholog
  17. 2022 Medium

    Coordinate regulation was demonstrated by linking zinc-importing ZIPs to ZnT1: ZIP4/ZIP5 elevate cell-surface ZNT1, and zinc-driven MTF-1 increases GluN2A-ZnT1 interactions to enhance NMDAR inhibition, integrating import, gene expression, and channel modulation.

    Evidence ZIP4/ZIP5 overexpression/depletion in polarized cells; MTF-1 reporter assays, Co-IP, peptide disruption, electrophysiology in neurons

    PMID:35513474 PMID:36202195

    Open questions at the time
    • Direct physical coupling of ZIPs and ZnT1 not shown in these studies
    • In vivo relevance of coordinated expression untested
  18. 2023 High

    Three studies expanded ZnT1's interaction and disease landscape: it binds the VGCC beta-subunit and Raf-1 to coordinate L-type/T-type channel crosstalk, controls endosomal zinc for TLR4/PD-L1 endocytosis in macrophages, and harbors aldosteronism-causing in-frame deletions that induce pathological Na+ influx.

    Evidence Co-IP and electrophysiology in oocytes/mammalian cells; myeloid-specific KO mice with endocytosis assays; NGS and inducible adrenal-cell expression with ion/Ca2+/CYP11B2 readouts

    PMID:37193665 PMID:37709865 PMID:37816045

    Open questions at the time
    • Structural basis of beta-subunit/Raf-1 binding unmapped
    • How zinc-binding-site deletions confer Na+ permeability not structurally resolved
  19. 2024 High

    Structure and in vivo genetics converged: cryo-EM defined a SLC30A-unique transport mechanism with His43 governing zinc selectivity, and intestinal-specific knockout impaired survival, while myeloid knockout confirmed zinc export enables NO-mediated antibacterial killing.

    Evidence Cryo-EM and His43 mutagenesis with intestinal-specific KO mice; Lyz2-Cre conditional KO with Salmonella infection, NF-kB/NO/zinc readouts

    PMID:39422023 PMID:39475776

    Open questions at the time
    • Conformational cycle of transport not captured in multiple states
    • Whether signaling functions are retained in structural mutants untested
  20. 2026 Medium

    ZnT1 was shown to physically interact with importers ZIP3 and ZIP1, and co-expression enhanced Zn2+ efflux, supporting a local Zn2+-cycle model in which ZIP-generated microdomains feed ZnT1 export.

    Evidence Co-IP, co-expression efflux assays in SH-SY5Y cells, immunofluorescence in cochlear nucleus and hippocampus

    PMID:41779239

    Open questions at the time
    • Direct microdomain measurement not shown
    • Stoichiometry and interface of ZIP-ZnT1 complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZnT1's intracellular C-terminal domain mechanistically engages Raf-1 and ion channels, and whether transport, channel regulation, and signaling are co-regulated at the structural level, remain unresolved.
  • No structure of the CTD bound to Raf-1 or a calcium channel
  • Stoichiometry and conformational coupling between transport and signaling unknown
  • In vivo importance of the signaling functions versus the transport function not separated genetically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0098772 molecular function regulator activity 4 GO:0140104 molecular carrier activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3 R-HSA-112316 Neuronal System 2 R-HSA-1643685 Disease 2
Partners
CACNBGLUN2AMTF1RAF1ZIP1ZIP3ZIP4

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 ZnT-1 functions as a Zn2+/H+ exchanger to extrude zinc from mammalian cells. Active-site mutagenesis of two amino acids in the putative zinc-binding domain abolished Zn2+ efflux and eliminated protection against Zn2+ toxicity. Efflux was sodium-independent, pH-driven, and calcium-sensitive. Fluorescent imaging (FluoZin-3, Fura-2) in HEK293T cells, active-site mutagenesis, homology modeling based on YiiP crystal structure Metallomics High 24951051
2021 In primary mouse cortical neurons, ZnT1 functions as a Zn2+/Ca2+ exchanger rather than a Zn2+/H+ exchanger. Knockdown via AAV-shZnT1 increased rates of Zn2+ rise and decreased rates of Zn2+ removal. Elimination of extracellular Ca2+ abolished Zn2+ efflux; increased extracellular Ca2+ enhanced efflux. Intracellular Ca2+ rises (measured by GCaMP6) paralleled cytoplasmic Zn2+ removal. AAV-shRNA knockdown in primary cortical neurons, FluoZin-3 fluorescence imaging, GCaMP6 Ca2+ imaging, ion substitution experiments Cell calcium High 34871934
2017 ZnT-1 is a dual-function protein: its Zn2+/H+ transport activity and its inhibition of the L-type calcium channel (LTCC) are structurally independent functions. Mutations in membrane-spanning helices that abolish zinc transport do not prevent LTCC inhibition. The intracellular C-terminal domain alone (lacking all ion-transfer segments) inhibits LTCC as efficiently as wild-type ZnT-1. Site-directed mutagenesis, truncation constructs, electrophysiology in Xenopus oocytes and mammalian cells Metallomics High 28091657
2004 ZnT-1 reduces intracellular zinc by modulating influx rather than accelerating efflux. Co-expression of ZnT-1 with the L-type calcium channel (LTCC) reduced the rate of zinc influx ~3-fold in HEK293 and PC-12 cells. ZnT-1 expression did not alter LTCC protein levels, indicating functional rather than expressional regulation of the channel. Fluorescent zinc transport measurements in HEK293/PC-12 cells, immunoblot for LTCC expression, overexpression of ZnT-1 with LTCC Biochemical and biophysical research communications Medium 15451416
2006 ZnT-1 silencing (siRNA) in cortical neurons caused ~70% reduction in ZnT-1 expression, increased Ca2+ influx via LTCC ~4-fold, increased synaptic release ~30%, and increased Zn2+ and Cd2+ influx rates through LTCC. This established ZnT-1 as a regulator of cation permeation through L-type Ca2+ channels in neurons. siRNA knockdown, fluorescent Ca2+/Zn2+/Cd2+ influx measurements, FM1-43 synaptic release assay in cortical neurons and granulosa cells Journal of molecular medicine Medium 16741752
2006 ZnT-1 overexpression or siRNA silencing in cultured cardiomyocytes decreased or increased (respectively) barium influx through LTCC. Co-expression in Xenopus oocytes decreased whole-cell barium current. Rapid pacing increased ZnT-1 protein expression and inhibited LTCC; silencing ZnT-1 prevented pacing-induced LTCC inhibition. In vivo atrial pacing of rats increased atrial ZnT-1 expression in parallel with decreased refractory period. Overexpression and siRNA knockdown in cardiomyocytes, Xenopus oocyte electrophysiology, in vivo rat atrial pacing, Western blot Cell calcium High 17196651
2011 ZnT-1 protects cardiomyocytes from ischemia-reperfusion injury through its C-terminal domain-mediated activation of Raf-1 kinase and downstream ERK signaling. A C-terminal truncation abolished ERK activation and cardioprotection, whereas expression of the C-terminal domain alone was sufficient for both. MEK inhibitor PD98059 abolished the protective effect. Overexpression and knockdown in HL-1 cardiomyocytes, truncation constructs, LDH release and caspase activation assays, phospho-ERK immunoblot, MEK inhibitor Journal of molecular medicine High 22193398
2012 ZnT-1 enhances T-type calcium channel (CaV3.1 and CaV3.2) activity and plasma membrane surface expression through Ras-ERK signaling. Co-expression of non-active Raf-1 blocked ZnT-1-mediated ERK phosphorylation and abolished T-type current augmentation. MEK inhibitor PD-98059 abolished the ZnT-1-induced increase in CaV3.1 surface expression (measured by biotinylation and TIRF microscopy). Xenopus oocyte electrophysiology, CHO cell overexpression, surface biotinylation, TIRF microscopy, dominant-negative Raf-1, MEK inhibitor PD-98059 American journal of physiology. Cell physiology High 22572848
2023 ZnT1 binds the auxiliary β-subunit of voltage-gated calcium channels (VGCC) and Raf-1 kinase, mediating crosstalk between LTCC and T-type calcium channels. The VGCC β-subunit inhibits ZnT1-induced augmentation of T-type channel (TTCC) function by reducing ZnT1-induced Ras-ERK activation. This effect is specific to ZnT1, as the β-subunit did not affect endothelin-1-induced TTCC surface expression. Co-expression in Xenopus oocytes and mammalian cells, electrophysiology, co-immunoprecipitation, Western blot for phospho-ERK, surface expression assays Metallomics Medium 37193665
2020 Disruption of the ZnT1-GluN2A association by a cell-permeant peptide strongly reduced NMDAR inhibition by synaptic zinc in mouse dorsal cochlear nucleus synapses. Synaptic zinc inhibition of NMDARs required postsynaptic intracellular zinc, indicating that cytoplasmic zinc is transported by ZnT1 to the extracellular space near the NMDAR. This establishes a postsynaptic transporter mechanism (rather than purely presynaptic release/diffusion) for zinc inhibition of NMDARs. Cell-permeant peptide disruption of ZnT1-GluN2A interaction, electrophysiology in mouse dorsal cochlear nucleus slices, intracellular zinc manipulation Science advances High 32937457
2022 Intracellular zinc drives MTF-1 activity in cortical neurons, increasing ZnT1 expression and the number of GluN2A-ZnT1 interactions, thereby enhancing tonic zinc inhibition of NMDAR-mediated currents. This effect was absent when the ZnT1-GluN2A interaction was disrupted by a cell-permeable peptide, linking zinc-responsive gene expression to NMDAR modulation. MTF-1 reporter assays in cortical neurons, co-immunoprecipitation for GluN2A-ZnT1 interaction, cell-permeant peptide disruption, electrophysiology Neuroscience letters Medium 36202195
2000 MTF-1 is essential for both basal and metal-induced (zinc and cadmium) regulation of the ZnT1 gene. In vitro DNA-binding assays showed mouse MTF-1 binds avidly to two metal-response elements in the ZnT1 promoter. MTF-1 knockout mouse embryo fibroblasts showed loss of both basal and inducible ZnT1 expression. In vivo, MTF-1 knockout in mice reduced ZnT1 mRNA ~4-6-fold in visceral yolk sac. In vitro DNA-binding assay, MTF-1 knockout mouse embryo fibroblasts, transgenic MTF-1 knockout mice, in situ hybridization, mRNA induction assays The Journal of biological chemistry High 10952993
2019 Under zinc-sufficient conditions, ZNT1 accumulates on the plasma membrane. Under zinc-deficient conditions, plasma membrane ZNT1 is endocytosed and degraded through both proteasomal and lysosomal pathways. ZNT1 is N-glycosylated on Asn299 in the extracellular loop between TM domains V and VI; this modification affects stability (non-glycosylated ZNT1 is more stable) but not zinc efflux function or subcellular localization. Subcellular fractionation, proteasome/lysosome inhibitors, site-directed mutagenesis of Asn299, immunofluorescence, functional zinc resistance assays in human and vertebrate cells The Journal of biological chemistry High 31471319
2013 Cooperative functions of ZnT1, metallothionein (MT), and ZnT4 in the cytoplasm are required for full activation of tissue non-specific alkaline phosphatase (TNAP) in the early secretory pathway (ESP). In ZnT1−/−MT−/−ZnT4−/− cells, TNAP activity was significantly reduced despite increased cytosolic zinc. Activity was restored by re-expression of wild-type but not zinc transport-incompetent mutants of ZnT1, demonstrating that ZnT1's zinc transport activity specifically supports ESP zinc enzyme activation. Triple gene knockout cells, re-expression with wild-type and transport-deficient mutants, TNAP activity assay, zinc supplementation rescue experiments PloS one High 24204829
2024 Cryo-EM structure combined with site-specific mutagenesis of human SLC30A1 identified a zinc transport mechanism unique within the SLC30A family, with His43 as a critical residue for zinc selectivity. Intestinal Slc30a1 is localized to the basolateral membrane of intestinal epithelial cells by lineage tracing. Intestinal-specific knockout mice showed impaired survival, establishing that intestinal SLC30A1 is essential for systemic zinc homeostasis. Cryo-EM structure determination, site-directed mutagenesis of His43, tissue-specific knockout mice (intestinal), lineage tracing for localization Advanced science High 39422023
2021 Human ZnT1 and a variant were heterologously expressed in S. cerevisiae and purified. The purified hZnT1 variant displayed Zn2+/H+ antiporter activity in vitro. Small-angle X-ray scattering of the soluble C-terminal domain (CTD) showed it forms a dimer with a V-shaped core in solution. The hZnT1-CTD melting temperature increases at acidic pH. Heterologous expression in yeast, detergent purification, in vitro Zn2+/H+ antiporter activity assay, SAXS analysis of CTD Frontiers in chemistry Medium 33996761
2009 Drosophila ZnT1 (dZnT1) is essential for dietary zinc absorption and functions at the basolateral membrane of enterocytes. Gut-specific silencing caused lethality under zinc scarcity. Human ZnT1, but not ZnT7 or ZnT4, rescued zinc-acquiring defects from dZnT1 silencing, demonstrating functional conservation and specificity. RNAi in Drosophila (ubiquitous and gut-specific), overexpression of human ZnT1/ZnT7/ZnT4 rescue, immunofluorescence for basolateral localization, zinc tolerance assays FASEB journal High 19325039
2023 Somatic in-frame deletions in SLC30A1 (p.L51_A57del, p.L49_L55del) near the zinc-binding site (His43, Asp47) in TM domain II cause primary aldosteronism by inducing pathological Na+ influx in adrenal cells. The SLC30A1 L51_57del variant in a doxycycline-inducible adrenal cell system caused membrane depolarization, opening of voltage-gated Ca2+ channels, increased cytosolic Ca2+, and stimulation of CYP11B2 expression and aldosterone production. Next-generation sequencing, doxycycline-inducible expression system in adrenal cells, ion current measurements, cytosolic Ca2+ measurements, CYP11B2 mRNA and aldosterone assays Nature genetics High 37709865
2008 ZnT1 silencing by vector-based shRNA (~40% reduction) in cultured rat cortical neurons decreased Zn2+ efflux compared to control neurons, demonstrating that ZnT1 plays a direct role in Zn2+ efflux. ZnT1-dependent efflux was higher in the first 10 min, suggesting dependence on intracellular free Zn2+ concentration or outward Zn2+ gradient. Vector-based shRNA knockdown in primary cortical neurons, FluoZin-3 microfluorometry to track intracellular Zn2+, EDTA-mediated extracellular Zn2+ removal Neuroscience letters Medium 19095042
2000 PC12 cells stably overexpressing wild-type rat ZnT-1 exhibited enhanced Zn2+ efflux and reduced vulnerability to Zn2+-induced death compared to parental cells. Cells expressing dominant-negative ZnT-1 showed opposite characteristics (reduced efflux, increased vulnerability). Zn2+ entered PC12 cells through L-type Ca2+ channels under depolarizing conditions. Stable cell line overexpression and dominant-negative expression, Zn2+ efflux assays, cell death assays (necrosis/apoptosis), L-type channel pharmacology Brain research Medium 11119691
2004 Heterologous expression of ZnT-1 in astrocytes slowed intracellular zinc accumulation and reduced sensitivity to toxic zinc levels, functionally demonstrating that ZnT-1 expression is sufficient to confer zinc protection in glial cells. Zinc pretreatment induced ~4-fold increase in endogenous ZnT-1 expression. Heterologous ZnT-1 expression in primary astrocytes, fluorescence cell imaging for intracellular zinc, cell viability assays, immunoblot Glia Medium 15378655
2020 In human monocyte-derived macrophages, LPS strongly upregulated SLC30A1 mRNA and protein. Ectopic SLC30A1 expression in THP-1 cells was sufficient to promote zinc-containing vesicle formation and localized to both plasma membrane and intracellular zinc-containing vesicles. SLC30A1-positive compartments subjected all contained bacteria to zinc stress, and SLC30A1 overexpression augmented zinc-mediated killing of intracellular E. coli. LPS stimulation, ectopic overexpression in THP-1 cells, fluorescent zinc vesicle imaging, E. coli zinc stress reporter, bacterial clearance assays, immunofluorescence for localization Journal of leukocyte biology Medium 32441444
2024 Myeloid-specific Slc30a1 conditional knockout mice showed increased susceptibility to attenuated Salmonella infection. Slc30a1-deficient macrophages exhibited defective intracellular killing, reduced NF-κB activation, and reduced nitric oxide production. Intracellular zinc accumulated in knockout macrophages, confirming Slc30a1 is required for zinc export, which in turn enables NO-mediated antibacterial activity. Lyz2-Cre conditional KO mice, Salmonella infection model, intracellular killing assays, NF-κB activation, NO measurement, intracellular zinc fluorescence eLife High 39475776
2023 ZNT1 in macrophages regulates endosomal zinc levels to control endocytosis of TLR4 and PD-L1. Myeloid-specific ZNT1 deletion in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. ZNT1-deficient macrophages showed impaired TLR4 and PD-L1 endocytosis, increasing macrophage-induced inflammation and immunosuppression. Myeloid-specific ZNT1 KO mice, liver tumor models, endocytosis assays for TLR4 and PD-L1, zinc supplementation experiments, immunofluorescence Hepatology High 37816045
2026 ZIP3 (in dorsal cochlear nucleus cartwheel cells) and ZIP1 (in hippocampal CA3 cells) physically interact with ZnT1. Co-expression of ZnT1 with ZIP3 or ZIP1 in SH-SY5Y cells enhanced Zn2+ efflux rates compared to ZnT1 alone, supporting a local Zn2+-cycle model where ZIP-mediated import generates intracellular Zn2+ microdomains near ZnT1 to support its activity. Co-immunoprecipitation for ZIP3/ZIP1-ZnT1 interaction, Zn2+ efflux assays in SH-SY5Y cells with co-expression, immunofluorescence in dorsal cochlear nucleus and hippocampus Cellular and molecular life sciences Medium 41779239
1998 Intestinal ZnT-1 protein was localized to the basolateral surface of enterocytes lining the villi of duodenum and jejunum by immunofluorescence. Dietary zinc supplementation elevated intestinal ZnT-1 mRNA and protein, while acute oral zinc dose upregulated mRNA without corresponding protein increase in intestine but increased protein in liver, demonstrating tissue-specific post-transcriptional regulation. Immunofluorescence for subcellular localization, Western blot, dietary zinc manipulation in rats Proceedings of the National Academy of Sciences Medium 9560190
2022 Overexpression of cell-surface-localized ZIP4 and ZIP5 increased cellular zinc content and caused increased cell-surface ZNT1 and cytosolic MT expression in the absence of added zinc. Elimination of overexpressed ZIP4/ZIP5 led to decreased ZNT1 expression but not MT expression, revealing differential protein-level regulation. In polarized cells, apically localized ZIP4 facilitated basolateral ZNT1 expression, establishing a coordinated expression mechanism for vectorial zinc transport. ZIP4/ZIP5 overexpression and depletion in cell lines, polarized cell models, zinc content measurement, Western blot for ZNT1 and MT Scientific reports Medium 35513474
2021 Slc30a1-deficient zebrafish show zinc accumulation in NC cells with increased stemness markers and upregulation of snai2 and jag1b. Knockdown of either snai2 or jag1b rescued pharyngeal arch development in Slc30a1-deficient zebrafish. The double zinc-finger domain of Snai2 was identified as a zinc-responsive element regulating jag1b expression, placing Slc30a1 upstream of a Snai2-Jag1b signaling axis in neural crest differentiation. Zebrafish Slc30a1a/b morpholino knockdown, SMART-seq transcriptomics, rescue experiments with snai2/jag1b knockdown, reporter assays for zinc-finger domain MedComm Medium 34977877
2019 Wild-type ZnT1 overexpression results in low intracellular zinc levels. Eight predicted functionally deleterious missense mutations in ZnT1, identified from cancer genomic databases, were validated as loss-of-function mutations: overexpression of these variants did not reduce intracellular zinc levels, confirming their functional impact. Novel functional zinc transport assays measuring cytosolic zinc levels, overexpression of WT and mutant ZnT1 in cell lines, bioinformatics analysis of COSMIC/gnomAD databases Cell death discovery Medium 31728210
2016 MTF1 knockdown in Caco-2 cells augmented the transcriptome response to zinc for most genes but abolished zinc-responsive regulation of ZnT1 and metallothionein genes specifically, demonstrating that MTF1 directly controls ZnT1 and MT expression to buffer cellular zinc homeostasis. siRNA-mediated MTF1 knockdown in Caco-2 cells, transcriptome analysis, metallothionein overexpression validation Metallomics Medium 26824222

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. The Journal of biological chemistry 325 10952993
1998 Regulation of the zinc transporter ZnT-1 by dietary zinc. Proceedings of the National Academy of Sciences of the United States of America 239 9560190
1997 Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil. The Journal of neuroscience : the official journal of the Society for Neuroscience 110 9254680
2019 Zinc transporter 1 (ZNT1) expression on the cell surface is elaborately controlled by cellular zinc levels. The Journal of biological chemistry 93 31471319
2007 Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. Journal of leukocyte biology 93 17971500
2000 L-type Ca(2+) channel-mediated Zn(2+) toxicity and modulation by ZnT-1 in PC12 cells. Brain research 88 11119691
2004 ZnT-1 expression in astroglial cells protects against zinc toxicity and slows the accumulation of intracellular zinc. Glia 84 15378655
2002 Distribution of the zinc transporter ZnT-1 in comparison with chelatable zinc in the mouse brain. The Journal of comparative neurology 81 11984815
2016 Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc. Metallomics : integrated biometal science 79 26824222
2009 Dietary zinc absorption is mediated by ZnT1 in Drosophila melanogaster. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 76 19325039
2006 Immunohistochemical analysis of ZnT1, 4, 5, 6, and 7 in the mouse gastrointestinal tract. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 76 17101726
2005 Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer's disease. Neurotoxicity research 71 16179263
2014 ZnT-1 extrudes zinc from mammalian cells functioning as a Zn(2+)/H(+) exchanger. Metallomics : integrated biometal science 68 24951051
2008 Zinc transporters ZnT1 (Slc30a1), Zip8 (Slc39a8), and Zip10 (Slc39a10) in mouse red blood cells are differentially regulated during erythroid development and by dietary zinc deficiency. The Journal of nutrition 65 18936201
2005 Zinc deficiency is associated with increased brain zinc import and LIV-1 expression and decreased ZnT-1 expression in neonatal rats. The Journal of nutrition 62 15867272
2006 Silencing of ZnT-1 expression enhances heavy metal influx and toxicity. Journal of molecular medicine (Berlin, Germany) 60 16741752
2004 A role for ZnT-1 in regulating cellular cation influx. Biochemical and biophysical research communications 60 15451416
2010 Increased level of exogenous zinc induces cytotoxicity and up-regulates the expression of the ZnT-1 zinc transporter gene in pancreatic cancer cells. The Journal of nutritional biochemistry 58 20392624
2020 Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1. Science advances 56 32937457
2023 Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism. Nature genetics 46 37709865
2003 Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein. Experimental biology and medicine (Maywood, N.J.) 42 12773700
2008 Silencing of ZnT1 reduces Zn2+ efflux in cultured cortical neurons. Neuroscience letters 41 19095042
2006 Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling. Cell calcium 37 17196651
2010 Characterization of the ER-located zinc transporter ZnT1 and identification of a vesicular zinc storage compartment in Hebeloma cylindrosporum. Fungal genetics and biology : FG & B 33 21134481
2019 Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer. Cell death discovery 32 31728210
2012 ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling. American journal of physiology. Cell physiology 32 22572848
2013 Cooperative functions of ZnT1, metallothionein and ZnT4 in the cytoplasm are required for full activation of TNAP in the early secretory pathway. PloS one 31 24204829
2011 ZnT-1 protects HL-1 cells from simulated ischemia-reperfusion through activation of Ras-ERK signaling. Journal of molecular medicine (Berlin, Germany) 31 22193398
2005 Zinc-regulating proteins, ZnT-1, and metallothionein I/II are present in different cell populations in the mouse testis. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 30 15995149
2008 ZnT-1, ZnT-3, CaMK II, PRG-1 expressions in hippocampus following neonatal seizure-induced cognitive deficit in rats. Toxicology letters 29 19059322
2002 Postnatal regulation of ZnT-1 expression in the mouse brain. Brain research. Developmental brain research 29 12220707
2018 MiR-411 suppresses the development of bladder cancer by regulating ZnT1. OncoTargets and therapy 27 30584327
2022 Sophisticated expression responses of ZNT1 and MT in response to changes in the expression of ZIPs. Scientific reports 25 35513474
2021 ZnT1 is a neuronal Zn2+/Ca2+ exchanger. Cell calcium 25 34871934
2009 Regulation of metallothioneins and ZnT-1 transporter expression in human hepatoma cells HepG2 exposed to zinc and cadmium. Toxicology in vitro : an international journal published in association with BIBRA 25 19900532
2023 ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor. Hepatology (Baltimore, Md.) 23 37816045
2017 Zinc transport and the inhibition of the L-type calcium channel are two separable functions of ZnT-1. Metallomics : integrated biometal science 21 28091657
2007 Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study. Journal of cardiovascular electrophysiology 21 17971132
2020 Frontline Science: LPS-inducible SLC30A1 drives human macrophage-mediated zinc toxicity against intracellular Escherichia coli. Journal of leukocyte biology 20 32441444
2019 The transporters SLC35A1 and SLC30A1 play opposite roles in cell survival upon VSV virus infection. Scientific reports 20 31320712
2017 Expression Patterns and Correlations with Metabolic Markers of Zinc Transporters ZIP14 and ZNT1 in Obesity and Polycystic Ovary Syndrome. Frontiers in endocrinology 19 28303117
2003 Different induction of metallothioneins and Hsp70 and presence of the membrane transporter ZnT-1 in HepG2 cells exposed to copper and zinc. Toxicology in vitro : an international journal published in association with BIBRA 19 14599444
2007 Cortisol stimulates the zinc signaling pathway and expression of metallothioneins and ZnT1 in rainbow trout gill epithelial cells. American journal of physiology. Regulatory, integrative and comparative physiology 18 18077514
2024 The Intestinal Transporter SLC30A1 Plays a Critical Role in Regulating Systemic Zinc Homeostasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 39422023
2007 Expression of ZnT-1 (Slc30a1) and MT-1 (Mt1) in the conceptus of cadmium treated mice. Reproductive toxicology (Elmsford, N.Y.) 15 17669619
2021 Heterologous Expression and Biochemical Characterization of the Human Zinc Transporter 1 (ZnT1) and Its Soluble C-Terminal Domain. Frontiers in chemistry 14 33996761
2010 The correlation among the dynamic change of Zn2+, ZnT-1, and brain-derived neurotrophic factor after acute spinal cord injury in rats. Biological trace element research 14 20838921
2022 Intracellular zinc signaling influences NMDA receptor function by enhancing the interaction of ZnT1 with GluN2A. Neuroscience letters 13 36202195
2020 The Roles of ZnT1 and ZnT4 in Glucose-Stimulated Zinc Secretion in Prostate Epithelial Cells. Molecular imaging and biology 13 33140261
2006 Cadmium and zinc induction of ZnT-1 mRNA in an established carp cell line. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 13 16627006
2024 The zinc transporter Slc30a1 (ZnT1) in macrophages plays a protective role against attenuated Salmonella. eLife 10 39475776
2022 The correlation and role analysis of SLC30A1 and SLC30A10 in cervical carcinoma. Journal of Cancer 10 35154468
2020 Drosophila ZnT1 is essential in the intestine for dietary zinc absorption. Biochemical and biophysical research communications 10 33012507
2011 The effects of transformation and ZnT-1 silencing on zinc homeostasis in cultured cells. The Journal of nutritional biochemistry 10 21775119
2019 MiRNA-8073 targets ZnT1 to inhibit malignant progression of ovarian cancer. European review for medical and pharmacological sciences 8 31364107
2010 The involvement of ZnT-1, a new modulator of cardiac L-type calcium channels, in [corrected] atrial tachycardia remodeling. [corrected]. Annals of the New York Academy of Sciences 8 20201890
2023 ZnT1 induces a crosstalk between T-type and L-type calcium channels through interactions with Raf-1 kinase and the calcium channel β2 subunit. Metallomics : integrated biometal science 6 37193665
2021 Metal transporter Slc30a1 controls pharyngeal neural crest differentiation via the zinc-Snai2-Jag1 cascade. MedComm 6 34977877
2016 ZNT-1 Expression Reduction Enhances Free Zinc Accumulation in Astrocytes After Ischemic Stroke. Acta neurochirurgica. Supplement 6 26463958
2021 HPV infection upregulates the expression of ZNT-1 in condyloma acuminatum. European journal of histochemistry : EJH 4 33908744
2024 Zinc Transporter ZnT1 mRNA Expression Is Negatively Associated with Leptin Serum Concentrations but Is not Associated with Insulin Resistance or Inflammatory Markers in Visceral Adipose Tissue. Biological trace element research 3 38319549
2011 Rapid homeostatic response of H4IIE cells to diethylenetriaminepentaacetic acid is not due to changes in the amount or localization of ZnT-1 protein. Nutrition research (New York, N.Y.) 3 21636019
2025 Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2 40113485
2022 Zinc transporter Slc30a1 regulates melanocyte development by interacting with mt2 in zebrafish. European journal of cell biology 2 36063588
2007 Age-dependent oxidation and aggregation of ZnT-1: a role for metal catalyzed oxidation? Experimental gerontology 2 17997256
2026 Piezo1 Regulates ZnT1-Mediated Zinc Homeostasis in Ulcerative Colitis. Inflammation 0 41586934
2026 ZIP-ZnT1 complexes mediate a local Zn2+-cycle regulating neuronal Zn²⁺ transport. Cellular and molecular life sciences : CMLS 0 41779239
2026 SLC30A1, SLC30A5, and SLC30A9 transporters play crucial role in ligand-independent activation of ESR1 signalling in breast cancer cells via modulation of AKT activity by zinc. Metallomics : integrated biometal science 0 41790496
2026 The role of zinc transporter 1 (ZnT1) in health and disease: From molecular mechanisms to therapeutic opportunities. European journal of medicinal chemistry 0 41833275
2025 Ginsenoside Ro alleviated cuproptosis induced by high oxalate via inhibiting zinc transporter ZnT1 in renal tubular epithelial cells. Journal of ginseng research 0 41550586
2024 ZNT1 Regulates the Proliferation, Migration and Invasion of HaCaT Cells Infected with HPV Through the PI3K/Akt Pathway. Indian journal of dermatology 0 38841228

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