Table 2.

ZnT transporters: location and regulation

Transporter	Tissue and cellular distribution	Stimulus	Response	Mechanism of response
ZnT1	Ubiquitous [41], with notable abundance in the duodenum, jejunum [42] and kidney [43] Plasma membrane (basolateral region in epithelial cells and apical region in pancreatic acinar cells) and vesicles [43, 44]	Increased cellular zinc in HepG2 cells [44, 45]	Increase in ZnT1 mRNA [44, 45]	Metal-response element-binding transcription factor-1 (MTF-1) binds to metal-response elements (MREs) in ZnT1 promoter [45]
		Zinc deficiency in HepG2 cells [45]	Decreased ZnT1 protein in HepG2 cells [45]	Endocytosis of cell surface ZnT1 with subsequent degradation via proteasomal or lysosomal pathways [45]
		Lipopolysaccharide in dendritic cells [44, 46]	Increase in ZnT1 mRNA [44, 46]	Process mediated via Toll/interleukin-1 receptor (TRIF) in Toll-like receptor (TLR) signalling [44, 46]
		T-cell stimulation by phytohaemagglutinin (immune activation) [47]	Downregulation of ZnT1 mRNA expression in T-cells [47]	–
ZnT2	Vesicles, secretory granules [43] Retina, mammary glands, small intestine, pancreas, kidney, prostate [44] Two variants: One variant is primarily located on the membranes of vesicles, including endosomes and lysosomes [44, 48] as well as zymogen granules in pancreatic acinar cells and the inner mitochondrial membrane in mammary cells [44] The other variant is localised to the plasma membrane [44, 48]	High zinc levels in mammary glands, prostate, pancreas, small intestine, kidney, and retina [44]	Upregulation of ZnT2 mRNA [44]	MTF-1 binding to MRE downstream from ZnT2 transcription start site [44, 49]
		Glucocorticoid hormone in pancreatic acinar cells [44]	Upregulation of ZnT2 transcription [44]	Glucocorticoid receptor and STAT5 interaction [44, 49]
		Prolactin in mammary epithelial cells [44]	Upregulation of ZnT2 transcription [50]	Prolactin induced JAK2/STAT5 signalling pathway [50]
			Decreased ZnT2 expression [44, 51]	Prolactin induced post-translational ZnT2 ubiquitination [44, 51]
ZnT3	Protein detected in brain, retina, and pancreas. RNA detected in testis, duodenum, airways and adipose tissue [52] On the membranes of synaptic vesicles [44, 53]	Angiotensin II in vascular smooth muscle cells [44, 54]	Downregulation of ZnT3 mRNA expression [54]	Angiotensin II leads to reactive oxidative species which is thought to downregulate ZnT3 [54]
ZnT4	Ubiquitous, with greater abundance in the brain and digestive tract [44] Trans-golgi network, cytoplasmic vesicles, endosomes, lysosomes, and Golgi apparatus [44]	Increased extracellular zinc [43]	Expression may not be affected but ZnT4 trafficking is induced [43]	Trafficking occurs from trans-golgi network to cytoplasmic vesicular compartment in cultured NRK cells [43]
		T-cell stimulation by phytohaemagglutinin (immune activation) [47]	Downregulation of ZnT4 mRNA expression in T-cells [47]	–
		Lipopolysaccharide in dendritic cells [46]	Upregulated expression of ZnT4 mRNA transcripts [46]	This is mediated via Toll/interleukin-1 receptor (TRIF) and myeloid differentiation primary response 88 (MyD88) protein in Toll like receptor (TLR) signalling [46]
		Granulocyte–macrophage colony-stimulating factor in macrophages [44]	Upregulation of ZnT4 mRNA expression [44]	–
		Cell differentiation in villus of small intestine [43, 44]	Increased ZnT4 expression [44]	–
ZnT5	ZnT5 mRNA was found in human endocrine pancreas, prostate and testis [55]. Also found in small intestine [56] Two variants: Variant A is located at the Golgi apparatus [57] Variant B is a bidirectional transporter located throughout the cell, including at the plasma membrane [44, 57] and is on the apical surface of enterocytes [58]	High or low zinc levels [43]	Increased expression [43] Decreased expression [43]	Increased mRNA stability [43] Transcriptional repression [43], which is under control of the zinc transcriptional regulatory element (ZTRE) [44]
		Lipopolysaccharide in mice liver [59]	Increased ZnT5 mRNA [59]	–
ZnT6	Protein detected in mouse brain, lung, small intestine, and kidney [60] Trans-golgi network, Golgi apparatus [44, 60]	T-cell stimulation by phytohaemagglutinin (immune activation) [47]	Downregulation of ZnT6 mRNA expression in T-cells [47]	–
		Lipopolysaccharide in dendritic cells [46]	Upregulation in ZnT6 mRNA expression [46]	Mediated through the Toll/interleukin-1 receptor (TRIF) and myeloid differentiation primary response 88 (MyD88) protein in Toll-like receptor (TLR) signalling [46]
ZnT7	In mice, protein was found in lung and small intestine. The mRNA was found in liver, kidney, spleen, heart, brain, small intestine, and lung, with abundant expression in small intestine and liver and less expression in heart [61] Early secretory pathway including Golgi apparatus [44]	T-cell stimulation by phytohaemagglutinin (immune activation) [47]	Downregulation of ZnT7 mRNA expression in T-cells [47]	–
		Granulocyte–macrophage colony-stimulating factor in macrophages [44]	Upregulation of ZnT7 mRNA expression [44]	–
ZnT8	Pancreas [62]; pancreatic β-cell-specific zinc transporter [44] on the membranes of insulin secretion granules [63]	Acute exposure to cytokines (including IL-1β, IFN-γ, IL-17, TNFα) in EndoC-βH1 cells [64]	Downregulation of ZnT8 protein [64]	–
ZnT10	Liver, brain [62] and intestine [65] Early/recycling endosomes, Golgi apparatus but can localise to plasma membrane under high extracellular zinc concentrations [44]	IL-6 in human SH-SY5Y neuroblastoma cells [44]	Decrease in both ZnT10 mRNA and protein levels [66]	IL-6 may affect the transcription of the SCL30A10 (gene encoding ZnT10), possibly involving a regulation element [66] which is suggested to be the ZTRE [44]
		Angiotensin II in vascular smooth muscle cells [44, 54]	Downregulation of ZnT10 mRNA expression [54]	Angiotensin II leads to reactive oxidative species which is thought to downregulate ZnT10 [54]
		High manganese intake in mice [67]	Increased ZnT10 protein levels in liver and small intestine in male mice [67]	–
		High extracellular zinc levels in human 5Y5Y neuroblastoma cells [68]	Downregulation of ZnT10 mRNA [68]	A zinc responsive element (ZRE) may be involved in ZnT10 downregulation [68]