Robert A. Colvin

Bio: Robert A. Colvin is an academic researcher from Ohio University. The author has contributed to research in topics: Zinc & Intracellular. The author has an hindex of 18, co-authored 36 publications receiving 1541 citations.

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.

Insights into Zn2+ homeostasis in neurons from experimental and modeling studies.

Abstract: To understand the mechanisms of neuronal Zn2+ homeostasis better, experimental data obtained from cultured cortical neurons were used to inform a series of increasingly complex computational models...

Sodium/Calcium Exchange: Its Physiological Implications

Abstract: The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

The neurobiology of zinc in health and disease

Abstract: The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

The Essential Toxin: Impact of Zinc on Human Health

Abstract: Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.