Zinc in Cellular Regulation: The Nature and Significance of "Zinc Signals"

Abstract

In the last decade, we witnessed discoveries that established Zn²⁺ as a second major signalling metal ion in the transmission of information within cells and in communication between cells. Together with Ca²⁺ and Mg²⁺, Zn²⁺ covers biological regulation with redox-inert metal ions over many orders of magnitude in concentrations. The regulatory functions of zinc ions, together with their functions as a cofactor in about three thousand zinc metalloproteins, impact virtually all aspects of cell biology. This article attempts to define the regulatory functions of zinc ions, and focuses on the nature of zinc signals and zinc signalling in pathways where zinc ions are either extracellular stimuli or intracellular messengers. These pathways interact with Ca²⁺, redox, and phosphorylation signalling. The regulatory functions of zinc require a complex system of precise homeostatic control for transients, subcellular distribution and traffic, organellar homeostasis, and vesicular storage and exocytosis of zinc ions.

Keywords: homeostasis; regulation; signalling; zinc.

Figure 1

Biological regulation with the three redox-inert metals ions: Mg²⁺, Ca²⁺, and Zn²⁺. Zinc extends the range of regulation with metal ions. The regulatory function of each metal ion is in a specific range of concentrations, thus avoiding overlap with the signalling functions of the other metal ions. However, there are interactions among the metabolism of the metal ions.

Figure 2

Control of cellular zinc homeostasis including regulation of zinc and functions of zinc in regulation. (1) Tier 1: cellular homeostasis through import and export through the plasma membrane and subcellular distribution; (2) Tier 2: vesicular storage and/or release of zinc associated with zinc importers and exporters on the vesicles; (3) Tier 3: loading of secretory vesicles with zinc associated only with zinc exporters on the vesicles. Regulatory functions of zinc require additional complexity in homeostatic control, namely, molecules that control the spatiotemporal fluctuations of zinc ions in a metal-buffered environment, above the fluxes in re-distributing zinc for supply as a cofactor in catalytic and structural sites of proteins. With this distinction, we assume that the functions of bona fide zinc proteins are not regulated by zinc coming on and off from their catalytic and structural sites. (Figures were composed from Servier Medical Art templates (http://smart.servier.com/)).

Figure 3

Cellular zinc transients and their control. Several pathways generate rapid zinc transients (zinc signals) with biological responses on various time scales. The amplitude of these zinc signals is about a few nanomolar globally, from picomolar basal “free” zinc ion concentrations, but may be higher in microdomains. Proteins involved in the control of zinc homeostasis serve as mufflers (ZIPs, ZnTs) and buffers (MTs) to restore the steady-state. A much slower process (arrow) leads to an overall change of the zinc-buffering characteristics of the cell, establishing different basal levels of “free” zinc ion concentrations.

Figure 4

Genomic effects as a consequence of sensing zinc signals. MTF-1 induces the expression of the zinc exporter ZnT1 (muffler) and MT (buffer), which adjust the cellular zinc buffering capacity, and other proteins. In addition, constitutively expressed zinc transporters and MTs control the zinc signals.