Mechanism and regulation of cellular zinc transport

Abstract

Zinc is an essential cofactor for the activity and folding of up to ten percent of mammalian proteins and can modulate the function of many others. Because of the pleiotropic effects of zinc on every aspect of cell physiology, deficits of cellular zinc content, resulting from zinc deficiency or excessive rise in its cellular concentration, can have catastrophic consequences and are linked to major patho-physiologies including diabetes and stroke. Thus, the concentration of cellular zinc requires establishment of discrete, active cellular gradients. The cellular distribution of zinc into organelles is precisely managed to provide the zinc concentration required by each cell compartment. The complexity of zinc homeostasis is reflected by the surprisingly large variety and number of zinc homeostatic proteins found in virtually every cell compartment. Given their ubiquity and importance, it is surprising that many aspects of the function, regulation, and crosstalk by which zinc transporters operate are poorly understood. In this mini-review, we will focus on the mechanisms and players required for generating physiologically appropriate zinc gradients across the plasma membrane and vesicular compartments. We will also highlight some of the unsolved issues regarding their role in cellular zinc homeostasis.

Figure 1

A schematic representation on the mechanisms of zinc homeostasis in mammalian cells. Zinc is distributed at large transmembrane and vesicular gradients. These are generated by the orchestrated activity of multiple zinc transporters and regulators of zinc transport. For the sake of simplicity, the ZnT2-10 have been illustrated on a single compartment although they may be found on multiple organelles.

Figure 2

Expression of ZnT-1 is followed by attenuation of Zn²⁺ influx and toxicity. A. HEK-293 cells were co-transfected with ZnT-1 and LTCC plasmids, or with LTCC only. Cells were loaded with Fura-2 (5 μM), which is also a highly sensitive Zn²⁺ dye, and imaged while superfusing with a high K⁺ Ringer’s solution (50mM) thereby opening the LTCC in the presence of Zn²⁺ (200 μM). B. Neurons were transfected with a ZnT-1 siRNA construct or control siRNA. Zn²⁺ (200 μM) was applied to a neuronal culture in the presence of high K ⁺ Ringer’s (ten minutes). Cell death was determined 24 h later using LDH.