The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Abstract

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn(2+)) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn(2+) activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular Zn(2+) levels are largely regulated by metallothioneins (MTs), Zn(2+) importers (ZIPs), and Zn(2+) transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn(2+). However, these regulatory actions of Zn(2+) are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn(2+) levels, Zn(2+)-mediated signal transduction, impacts of Zn(2+) on ion channels and mitochondrial metabolism, and finally, the implications of Zn(2+) in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn(2+).

Keywords: Metallothionein; Signal Transduction; Zinc; Zinc exporter; Zinc importer.

Fig. 1. Impact of Zn²⁺ concentration on protein function in the cell. The total zinc concentration in a eukaryotic cell is relatively high (100~300 µM), but the actual amount of Zn²⁺ ranges from ~pM to ~nM values, depending on the cell type. Both extremely low and extremely high levels of Zn²⁺ have adverse effects on the cell. Excess Zn²⁺ causes irreversible effects on proteins, such as aggregation, which leads to the dysfunction of many proteins. Low levels of Zn²⁺ are also detrimental to the cell, since it is an important metal cofactor and signal transducer.

Fig. 2. Subcellular localization of Zn²⁺ transporters. Zinc absorbed in the intestine as an ion goes into the blood stream. Serum albumin is a major Zn²⁺ binding protein and serves as a macro Zn²⁺ transporter to target tissues; thus, changes in the concentration of albumin or an increase of fatty acids, which interferes with Zn²⁺ binding to albumin, impairs the control of blood Zn²⁺ levels. The availability of intracellular Zn²⁺ is governed by the action of MTs (MTs; binding or trapping of Zn²⁺), zinc transporters (ZnTs; Zn²⁺ efflux), Zn²⁺ importers (ZIPs; Zn²⁺ influx) residing in the plasma membrane, redox potential, pH, and other unknown modulators. ZIPs and ZnTs residing in the organelle membrane have an inverse direction compared to those located in the plasma membrane. The activation of metalresponsive-element-binding transcription factor-1 (MTF-1) increases the expression of MTs, and thereby reduces Zn²⁺ levels upon binding to Zn²⁺. Specific forms of MTs, ZnTs, and ZIPs are dependent on cell-type, which will give varying responses, even at the same zinc levels. Extracellular Zn²⁺ entering the cell could be immediately buffered within the still undefined 'zinc muffler' and translocated into an intracellular Zn²⁺ store, such as the endoplasmic reticulum (ER) and Golgi apparatus by ZnT. Inversely, Zn²⁺ released into the cytosol from Zn²⁺ stores by ZIPs is also buffered by a cytosolic Zn²⁺ muffler. Arrows show the predicted direction of Zn²⁺ mobilization.

Fig. 3. Roles of Zn²⁺ in a biological system. Various tissues and organs are influenced by Zn²⁺. The intracellular Zn²⁺ levels are primarily regulated by MTs, ZnTs, and ZIPs. The action of Zn²⁺ can be initiated within a few minutes by protein modification involved in enzyme activities and signal transduction, or in late events, which are mediated by gene regulation. Therefore, the impairment of Zn²⁺ homeostasis, such as deficiency or excess, can lead to cellular malfunction, and eventually, cell damage.