The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Abstract

Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

“…Because in most cells the primary buffers for Mg 2+ are phosphonucleotides (22), the metabolic state potentially regulates TRPM7 activity as ATP levels rise and fall around 0.5 mM. Under normal circumstances, the driving force for Mg 2+ entry into cells is relatively low ( ] in organelles and the cytosol (23). TRPM7's Zn 2+ conductance suggests that it could support rapid changes in cytoplasmic Zn 2+ levels under the right circumstances, either across the plasma membrane or from intracellular compartments.…”

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

“…Although Zip9 mRNA expression was also increased by the HFD (Fig. 5A), its hepatic abundance is known to be low (16); thus, it is unlikely that ZIP9 contributes markedly to hepatic zinc uptake. This conclusion 65 Zn uptake (C) in WT and Zip14 KO mice (n = 3-4) are shown after administration of TM (2 mg/kg) or vehicle.…”

“…To maintain zinc homeostasis, mammalian cells use 24 known zinc transporters that tightly control the trafficking of zinc in and out of cells and subcellular organelles. These transporters are within two families: ZnT (Zinc Transporter; SLC30) and ZIP (Zrt-, Irt-like protein; SLC39) (16)(17)(18). Physiological stimuli have been shown to regulate the expression and function of some of these transporters.…”

Identification of Genetic Diseases Using Breast Milk Cell Analysis: The Case of Transient Neonatal Zinc Deficiency (TNZD)

“…Acrodermatitis Enteropathica (AEZ; OMIM #201100) is an autosomal recessive disease [12,13] which presents after weaning. Acrodermatitis Enteropathica is a result of loss of function mutations in the zinc transporter Zip4 (SLC39A4), which leads to impaired intestinal absorption of zinc [14].…”