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. 2023 Oct 17;101(16):714-720.
doi: 10.1212/WNL.0000000000207912.

What Are the Functions of Zinc in the Nervous System?

Eduardo Benarroch

What Are the Functions of Zinc in the Nervous System?

Eduardo Benarroch. Neurology. .
No abstract available

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure
Figure. Regulation and Functions of Zinc in the Nervous System
Zinc (Zn) is released from glutamatergic terminals, functions as an intracellular signaling molecule, and is a structural and regulatory catalyst ion for Zn-finger proteins including enzymes and transcription factors. Zinc homeostasis is tightly regulated by Zn transport proteins of the ZIP (SLC30) and ZnT (SLC39) families and by its buffering by metallothioneins (MTs), particularly MT-III. Metal-regulatory transcription factor 1 (MTF1) is activated by cytosolic Zn2+ and promotes transcription of genes encoding MTs and ZnT transporters while repressing expression of most ZIP genes. Zinc is transported into synaptic vesicles of glutamatergic neurons through ZnT3 which is cotargeted with the vesicular glutamate transporter 1 (VGLUT1). Zinc functions as an allosteric inhibitor of GluN2A subunit containing N-methyl-D-aspartate receptors (NMDARs). The inhibitory effect of intracellular Zn2+ on this receptor is antagonized by Zn2+ export by ZnT1 coupled to the GluN2A. Zinc has bidirectional effect on α-amino-3-hydroxyl-5methyl-4-isoxazole receptors (AMPARs) (not shown). Zinc also allosterically inhibits extrasynaptic γ-aminobutyric acid (GABA)A receptors (GABAARs). Zinc can enter their postsynaptic targets through Ca2+ permeable AMPARs (CA-AMPARs), NMDARs, Cav1 (L-type) Ca2+ channels, and transient receptor potential (TRP) melastatin 7 (TRPM7) channels. Intracellular Zn2+ upregulates Kv7 (KCNQ) and large conductance Ca2+ activated K+ (BK) channels and inhibits TRP vanilloid type 1 channels (not shown) and either facilitating or inhibiting acid-sensing ion channels depending on their subtype (not shown). Zn2+ activates its own metabotropic G-protein coupled receptor (GPR39, mZnR), which is coupled to a Gq and triggers release of Ca2+ from intracellular stores and downstream signaling through extracellular signal-regulated kinase (ERK), calmodulin kinase II, protein kinase C (PKC), and phosphatidylinositol 3-kinase/AKT (protein kinase B). This receptor also upregulates the potassium (K+)/chloride (Cl−) cotransporter 2 (KCC2) resulting in a switch on the chloride (Cl−) equilibrium potential that promotes GABAAR-mediated inhibition. Intracellular Zn2+ functions as a second messenger that activates protein kinases, such as components of the Ras mitogen activated protein kinase (MAPK)/ERK pathway, protein kinase C (PKC), AKT (protein kinase B), and Src tyrosine kinase. Through Src kinase, Zn2+ transactivates tropomyosin-related kinase B (TrkB) thus contributing to neuronal survival and synaptic plasticity. Zinc activates superoxide dismutase (SOD) involved in antioxidant defense. Zinc-finger proteins are involved in DNA recognition and repair, RNA metabolism, and proteostasis. Accumulation of intracellular-free Zn2+ leads to activation of cascades that generate reactive oxygen species (ROS), including those mediated by lipoxygenase (LOX) and nicotinamide adenine dinucleotide phosphate oxidases (NOX). Oxidative stress and nitric oxide (not shown) promote Zn2+ release from its binding to MT-III. Excessive cytosolic Zn2+ may be sequestered in mitochondria (Mit) through ZIP10 and lysosome (Lys) through ZnT4. ER, endoplasmic reticulum.
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