{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC30A3, which encodes the zinc transporter ZnT3, is predominantly localized to synaptic vesicles in excitatory neurons and plays an essential role in controlling synaptic zinc levels that are critical for proper cognitive function. Multiple studies have reported that altered SLC30A3 expression is associated with neurodegenerative and psychiatric conditions. Reduced SLC30A3 levels have been observed in Alzheimer’s disease—where zinc accumulation in amyloid plaques and synaptic loss are prominent—and in disorders such as schizophrenia and depression, with evidence even indicating gender‐specific genetic associations. Diminished SLC30A3 expression has additionally been noted in amyotrophic lateral sclerosis, underscoring its importance in neuronal zinc regulation and overall brain health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, SLC30A3 function is intricately regulated by its capacity to form intermolecular covalent dityrosine bonds. This oligomerization process modulates its targeting to synaptic‐like microvesicles and enhances the transporter’s ability to mitigate zinc toxicity. Notably, under conditions of oxidative stress the extent of dityrosine-mediated oligomer formation increases, and experimental knockdown of SLC30A3 leads to reduced activation of protective ERK1/2 signaling, thereby rendering cells more susceptible to endoplasmic reticulum stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its critical functions in the central nervous system, SLC30A3 exhibits tissue-specific expression patterns that suggest diverse roles in zinc homeostasis. In human pancreatic β-cells, for instance, SLC30A3 is uniquely detected and may contribute to zinc handling necessary for insulin synthesis and processing. Moreover, altered SLC30A3 levels have been implicated in non-neuronal pathologies: androgen-independent prostate cancer cells show increased SLC30A3 expression despite overall lower intracellular zinc levels, and in glioblastoma, epigenetic suppression of SLC30A3 is associated with enhanced tumor growth and metastasis through modulation of the MAPK signaling pathway. Variable expression in leukocytes further indicates that SLC30A3 regulation is nuanced across different cellular contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Li-Hong Zhang, Xin Wang, Meredin Stoltenberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abundant expression of zinc transporters in the amyloid plaques of Alzheimer's disease brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Res Bull (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.brainresbull.2008.03.014"}], "href": "https://doi.org/10.1016/j.brainresbull.2008.03.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18639746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18639746"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "C Perez-Becerril, A G Morris, A Mortimer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Allelic variants in the zinc transporter-3 gene, SLC30A3, a candidate gene identified from gene expression studies, show gender-specific association with schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Psychiatry (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.eurpsy.2013.05.007"}], "href": "https://doi.org/10.1016/j.eurpsy.2013.05.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23849395"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23849395"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "David R Whitfield, Julie Vallortigara, Amani Alghamdi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Depression and synaptic zinc regulation in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Geriatr Psychiatry (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jagp.2014.05.001"}], "href": "https://doi.org/10.1016/j.jagp.2014.05.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24953873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24953873"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "David R Whitfield, Julie Vallortigara, Amani Alghamdi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2014.06.015"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2014.06.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25104558"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25104558"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Masayuki Kaneko, Takao Noguchi, Saori Ikegami, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.23491"}], "href": "https://doi.org/10.1002/jnr.23491"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25284286"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25284286"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "C Perez-Becerril, A G Morris, A Mortimer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants in the chromosome 2p23 region containing the SLC30A3 (ZnT3) gene are associated with schizophrenia in female but not male individuals in a large collection of European samples."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatry Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.psychres.2016.09.052"}], "href": "https://doi.org/10.1016/j.psychres.2016.09.052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27750116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27750116"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Daniela Enache, Joana B Pereira, Vesna Jelic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased Cerebrospinal Fluid Concentration of ZnT3 Is Associated with Cognitive Impairment in Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-200498"}], "href": "https://doi.org/10.3233/JAD-200498"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32925049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32925049"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Gloria Salazar, Juan M Falcon-Perez, Robert Harrison, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SLC30A3 (ZnT3) oligomerization by dityrosine bonds regulates its subcellular localization and metal transport capacity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0005896"}], "href": "https://doi.org/10.1371/journal.pone.0005896"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19521526"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19521526"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hisaka Kurita, Rika Okuda, Kazuki Yokoo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protective roles of SLC30A3 against endoplasmic reticulum stress via ERK1/2 activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2016.09.119"}], "href": "https://doi.org/10.1016/j.bbrc.2016.09.119"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27678294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27678294"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kazuhiro Iguchi, Takashi Otsuka, Shigeyuki Usui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zinc and metallothionein levels and expression of zinc transporters in androgen-independent subline of LNCaP cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Androl (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/j.1939-4640.2004.tb02771.x"}], "href": "https://doi.org/10.1002/j.1939-4640.2004.tb02771.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14662799"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14662799"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Silke Overbeck, Peter Uciechowski, M Leigh Ackland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0307148"}], "href": "https://doi.org/10.1189/jlb.0307148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17971500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17971500"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Kamille Smidt, Agnete Larsen, Andreas Brønden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biometals (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10534-016-9915-7"}], "href": "https://doi.org/10.1007/s10534-016-9915-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26867900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26867900"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yimeng Cai, Catherine P Kirschke, Liping Huang "}, {"type": "b", "children": [{"type": "t", "text": "SLC30A family expression in the pancreatic islets of humans and mice: cellular localization in the β-cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Histol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10735-017-9753-0"}], "href": "https://doi.org/10.1007/s10735-017-9753-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29372370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29372370"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Longzhou Zhang, Zengjin Liu, Yang Dong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic targeting of SLC30A3 by HDAC1 is related to the malignant phenotype of glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "IUBMB Life (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/iub.2463"}], "href": "https://doi.org/10.1002/iub.2463"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33715270"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33715270"}]}]}]}