Cytosolic zinc buffering and muffling: Their role in intracellular zinc homeostasis

Abstract

Our knowledge of the molecular mechanisms of intracellular homeostatic control of zinc ions is now firmly grounded on experimental findings gleaned from the study of zinc proteomes and metallomes, zinc transporters, and insights from the use of computational approaches. A cell's repertoire of zinc homeostatic molecules includes cytosolic zinc-binding proteins, transporters localized to cytoplasmic and organellar membranes, and sensors of cytoplasmic free zinc ions. Under steady state conditions, a primary function of cytosolic zinc-binding proteins is to buffer the relatively large zinc content found in most cells to a cytosolic zinc(ii) ion concentration in the picomolar range. Under non-steady state conditions, zinc-binding proteins and transporters act in concert to modulate transient changes in cytosolic zinc ion concentration in a process that is called zinc muffling. For example, if a cell is challenged by an influx of zinc ions, muffling reactions will dampen the resulting rise in cytosolic zinc ion concentration and eventually restore the cytosolic zinc ion concentration to its original value by shuttling zinc ions into subcellular stores or by removing zinc ions from the cell. In addition, muffling reactions provide a potential means to control changes in cytosolic zinc ion concentrations for purposes of cell signalling in what would otherwise be considered a buffered environment not conducive for signalling. Such intracellular zinc ion signals are known to derive from redox modifications of zinc-thiolate coordination environments, release from subcellular zinc stores, and zinc ion influx via channels. Recently, it has been discovered that metallothionein binds its seven zinc ions with different affinities. This property makes metallothionein particularly well positioned to participate in zinc buffering and muffling reactions. In addition, it is well established that metallothionein is a source of zinc ions under conditions of redox signalling. We suggest that the biological functions of transient changes in cytosolic zinc ion concentrations (presumptive zinc signals) complement those of calcium ions in both spatial and temporal dimensions.

Zinc-induced self-association of complement C3b and Factor H: Implications for inflammation and age-related macular degeneration

“…Although the extracellular bioavailable zinc levels are yet to be precisely determined, indications are that these will also be in the nanomolar to picomolar range, similar to intracellular bioavailable zinc levels. Thus bioavailable zinc levels in plasma are in a range of 20 -210 pM (64). In plasma, the total zinc level remains steady at 14.7 M even after a daily diet supplement with 80 mg zinc in the AREDS trials (38).…”

Copper and zinc detoxification in Gammarus pulex (L.)

“…As metal concentrations in the heat-stable cytosol largely increased between days4 and16, there was no further increase in MTLP levels. Colvin and colleagues (Colvin et al, 2010) suggested that, with Zn at least, MT might be involved in buffering and muffling reactions that are caused by the Zn 2+ binding to MT with differing affinities. From this, we could postulate that, at day4, MTLPs had been induced following exposure, but the MTLPs were not saturated.…”

Synthetic Metallochaperone ZMC1 Rescues Mutant p53 Conformation by Transporting Zinc into Cells as an Ionophore

“…-10 210 M (Colvin et al, 2010;Yu et al, 2014). We therefore concluded that p53-R175H is nonfunctional in the cell because it is unable to bind Zn 21 under physiologic conditions.…”