Questions and Controversies in Zinc Signaling


Questions and Controversies in Zinc Signaling


Jan 26 2004 1:44PM

The STKE Editors

This Forum on zinc signaling is dedicated to the memory of John M.Sarvey, who died of complications of pancreatic cancer on August 20, 2003. With a long-time interest in hippocampal long-term potentiation, John hadmore recently become interested in the role of zinc in hippocampalsynaptic transmission and neurodegeneration and was actively directingresearch in this field at the time of his death. A delightful and engaging individual as well as an enthusiastic and inspiring colleague, John willbe deeply missed by his many friends and colleagues in the zinc signalingcommunity.

Opening Remarks

Jan 27 2004 6:19AM

Liz Adler

The discovery, many years ago, of zinc in the synaptic vesicles of some glutamatergic neurons--as well as various other secretory vesicles--inaugurated a lively and at times controversial field concerning the normal physiological role of the sequestered zinc, its involvement in neurodegeneration and excitotoxic cell death and in epilepsy, and the mechanisms whereby zinc achieves both its physiological and its pathological effects (see Frederickson). Among the various possible functions of synaptic zinc, one of the most fascinating is the notion that zinc released from presynaptic nerve terminals crosses the synapse to not only affect various channels and receptors but to enter the post-synaptic cell and modulate the activity of various signaling pathways (see Perspective by Li et al.). In contrast to this view, a recent article makes the provocative suggestion that, rather then being freely released into the synapse, the zinc associated with synaptic vesicles may be externalized to act as a "hook" for extracellular zinc-binding molecules (Kay).

Zinc has many functions far from the synapse, of course, and is well known for playing a structural role in stabilizing the zinc fingers found in many transcription factors and various signaling proteins. The recent observation that zinc fingers may act as sensors to regulate activation domain function of the yeast transcription factor Zap 1 (Bird et al.) adds a new twist to the role of these nucleic acid-binding domains. The observation that activation of protein kinase C (PKC) through two distinct pathways led to an increase in free intracellular zinc traced to the zinc finger domains of PKC and the intriguing suggestion that, far from playing a static role in stabilizing the zinc finger domain, zinc serves as "the linchpin that orchestrates dynamic changes in response to specific signals" in PKC activation (Korichneva et al.).

Feel free to raise questions related to zinc signaling, or to comment on any of the research discussed above--or on any other aspects of the zinc signaling field.

Opening Remarks

Feb 2 2004 8:11AM

Henry Fliss

Therapeutic potential of induced intracellular zinc transients

Zinc as an intracellular signaling agent is a concept whose time hasfinally arrived. In addition to the work of Bird at al. (1) and Korichneva et al., (2), cited in Dr. Adler’s opening remarks, other studies such asSmith et al. (3) and Sauer et al. (4) strongly suggest that intracellularzinc transients or fluxes have a pronounced regulatory effect on cellgrowth and apoptosis.

Our own studies tend to support this concept. We have shown thatphysiological oxidants can cause the release of intracellular zinc (5-7),and that this release transiently increases the intracellular “free” zincconcentration from roughly 200 pM to approximately 7 nM (8).

Proceeding on the assumption that such zinc transients represent anintracellular signaling mechanism, we examined the possibility that theinduction of artificial zinc transients in cells could trigger regulatoryeffects. Specifically, we examined the ability of zinc ionophores to block the apoptotic machinery in injured tissues. In a recent abstract, wedescribe the ability of very low doses of zinc ionophores such as zinc- pyrithione and zinc-diethyldithiocarbamate to block apoptosis and improvefunction in animal models of myocardial infarction and stroke (9).

We are currently continuing these promising studies in the setting of a new biotech company, Zinc Therapeutics, Inc. We believe that, much likecalcium transients, zinc transients act as a signaling “language” totrigger intracellular events. We anticipate that, once the words of thislanguage are deciphered, we will be able to “speak” to the cell using zinc ionophores.

I am hoping to initiate a discussion of this important therapeuticquestion. One question that may be of particular interest is:

How can one identify the target(s) of zinc transients given thathundreds of metalloproteins are known to interact with zinc?

Reference List

1. Bird,A.J., McCall,K., Kramer,M., Blankman,E., Winge,D.R., andEide,D.J. 2003. Zinc fingers can act as Zn2+ sensors to regulatetranscriptional activation domain function. EMBO J.22:5137-5146. [Abstract]

2. Korichneva,I., Hoyos,B., Chua,R., Levi,E., and Hammerling,U.2002. Zinc Release from Protein Kinase C as the Common Event duringActivation by Lipid Second Messenger or Reactive Oxygen. J.Biol.Chem.277:44327-44331. [Abstract]

3. Smith,P.J., Wiltshire,M., Davies,S., Chin,S.F., Campbell,A.K.,and Errington,R.J. 2002. DNA damage-induced [Zn2+]i transients:correlation with cell cycle arrest and apoptosis in lymphoma cells.Am.J.Physiol. 283:C609-C622. [Abstract]

4. Sauer,G.R., Smith,D.M., Cahalane,M., Wu,L.N., and Wuthier,R.E.2003. Intracellular zinc fluxes associated with apoptosis in growth platechondrocytes. J.Cell.Biochem. 88:954-969.

5. Fliss,H. and Ménard,M. 1992. Oxidant-induced mobilization of zinc from metallothionein. Arch.Biochem.Biophys. 293:195-199.

6. Fliss,H., Ménard,M., and Desai,M. 1991. Hypochlorous acidmobilizes cellular zinc. Can.J.Physiol.Pharmacol. 69:1686-1691.

7. Tatsumi,T. and Fliss,H. 1994. Hypochlorous acid mobilizesintracellular zinc in isolated rat heart myocytes. J.Mol.Cell.Cardiol.26:471-479.

8. Turan,B., Fliss,H., and Désilets,M. 1997. Oxidants increaseintracellular free Zn2+ concentration in rabbit ventricular myocytes.Am.J.Physiol. 272:H2095-H2106. [Abstract]

9. Gulyaeva,N., Stepanichev,M., Onufriev,M., Lazareva,N., andFliss,H. 2003. Zinc ionophores as neuroprotective agents. J.Neurochem. 85Suppl.2:27 (Abstr.)

Connecting Zinc to Apoptosis through BAK

Dec 22 2006 7:07AM

Nancy R Gough

An article in Molecular Cell by Moldeoveanu et al. suggests that the ability of Bak to promote mitochondrial outer membrane permeabilization is inhibited by zinc-induced dimerization. This provides a link between zinc concentrations and apoptosis, thereby expanding the roles for zinc in controlling cell physiology.

T. Moldoveanu, Q. Liu, A. Tocilj, M. Watson, G. Shore, K. Gehring, Thee X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol. Cell 24, 677-688 (2006). [Abstract]

New Evidence for Zinc in Synaptic Transmission

Dec 4 2006 8:15AM


In the November 22 issue of Neuron, Hirzel et al. report that mice containing a form of the glycine receptor alpha 1 subunit (GlyRalpha1) that cannot be potentiated by zinc show altered inhibitory neurotransmission. (see the Editors' Choice "Startled by a Lack of Zn2+ (Modulation)", for a summary of the article.)

As zinc targets may include the NMDA and GABAA receptors, as well as neurotransmitter transporters, these results are intriguing and the technique applied by Hirzel et al. may inspire new ways to investigate the roles of zinc in other types of synaptic activity.

What are the next steps in reconciling these studies with the GlyR that provide strong support for a physiological role for zinc in modulating neurotransmission and the lack of a strong phenotype associated with knocking out the gene encoding vesicular zinc transporter ZnT3?

Where is the zinc that binds the GlyR coming from? Is it tonic modulation or phasic modulation?

As with many important findings, the results of Hirzel et al. lead to more questions and open new avenues of investigation.


K. Hirzel, U. Müller, A. T. Latal, S. Hülsmann, J. Grudzinska, M. W. Seeliger, H. Betz, B. Laube, Hyperekplexia phenotype of glycine receptor α1 subunit mutation mice identifies Zn2+ as an essential endogenous modulator of glycinergic neurotransmission. Neuron 52, 679-690 (2006).

A. R. Kay, J. Neyton, P. Paoletti, A startling role for synaptic zinc. Neuron 52, 572-574 (2006).

Zinc Signals 2007

Jun 3 2007 6:42AM


The Zinc Signals 2007 8th International Conference, under the auspices of the Institute of Zinc in Biology, is underway at the Cook's Branch Conservancy, a private family-owned preserve in Montgomery County Texas.

In the Saturday morning session, Yang Li, Jing Qian, and Charles Zorumski discussed various aspects of zinc signaling in the hippocampus, ranging from interactions between zinc and calcium signals, to the effects of zinc on postsynaptic neuronal firing, to the possible role of zinc in metaplasticity. Richard Chappel continued the synaptic theme, but shifted focus from the hippocampus to the retina, describing research indicating that zinc functions as a vertebrate retinal neurotransmitter. David Soybel spoke about the relationship between zinc transport and H+ secretion in gastric parietal cells. Robert Colvin wrapped up the morning session with a talk on approaches to analyzing zinc metallanomics in resting neurons.

The Saturday afternoon session concentrated on zinc and the prostate, with talks by Fabrice Chimienti, Renty Franklin, and Christopher Frederickson on zinc and zinc transporters in the normal and malignant prostate and the possibility that zinc concentration in prostatic fluid might provide a diagnostic biomarker for prostate cancer.

Saturday's meeting concluded with a keynote speech by Nobel Laureate Ferid Murad, describing his research another molecule once thought to be "unconventional" and unlikely to be a key player in cell signaling, NO.

Reported by Elizabeth M. Adler

Zinc Signals 2007

Jun 4 2007 10:03AM


In the Sunday morning session on zinc sensors, Richard Thompson spoke about carbonic anhydrase-based fluorescence zinc sensors; Paul Bentleytalked about the development of new dipyrrin-based zinc probes; andLeonard Giblin spoke about issues related to dye-based methods ofmeasuring free zinc in complex medium (medium that contains componentsthat buffer zinc and compete with the dye for zinc binding). Carol Fierkenoted that some "zinc metalloenzymes" also bind exchangeable iron(typically present at higher intracellular concentrations thanexchangeable zinc) and discussed the intriguing notion that "metalswitching" could provide a novel mechanism for regulating the functionof such enzymes. Zeev Rosenzweig wrapped up the Sunday morning session byspeaking about the possibilities inherent in using modified surfaces, onwhich cells could be cultured, or targeted probes as optochemical sensorsfor detecting released zinc.

Wolfgang Maret started off the first afternoon session with adiscussion of the subtleties of metallothionein-zinc interaction, notingthat the seven metallothionein zinc-binding sites did not all have thesame binding affinity and that the zinc buffering capacity ofmetallothionein was affected by redox state. Hajo Haase discussed theeffects of zinc on the response of monocytes to LPS, describing the cellsignaling mechanisms whereby low concentrations of zinc could facilitatethe production of inflammatory cytokines and high concentrations of zinccould have an anti-inflammatory effect. Wojciech Bal spoke about anucleasomal zinc binding site and John Weiss discussed zinc disruption ofmitochondrial function and its possible role in ischemic injury inhippocampal pyramidal neurons.

Zinc deficiency leads to a syndrome characterized by growthretardation, immune dysfunction, and cognitive impairment. The secondSunday sesssion had talks by Harold Sandstead, on zinc nutriture,Katherine Lorenz, on the introduction of amaranth to combat malnutritionin Oaxaca, and Jane Flynn on implications of the relationship betweendietary copper and zinc for cognitive function.

The Sunday evening keynote speech was by Ananda Prasad, on hisdiscovery of the zinc deficiency syndrome, which affects some two billionpeople, and how zinc deficiency affects immune function.

Reported by Elizabeth M. Adler

Zinc Signals 2007

Jun 5 2007 1:07PM


Arie Moran opened the final session, on Monday morning, with a talk on ZnT-1 modulation of calcium current in cardiac myocytes and the possible implications for atrial fibrillation. Irina Korichneva continued the cardiac theme, discussing zinc and PKC activation in the heart and the protective effect of zinc in myocardial ischemia and reperfusion. In the final talk of the meeting, Jae Koh discussed pathways involved in the death of neurons overloaded with zinc.

Overall, the meeting underlined the many roles for intracellular zinc and the interdisciplinary nature of current research into the biology of zinc signaling.

Reported by Elizabeth M. Adler

First Meeting of the Society for Zinc Biology

Jun 13 2007 11:51AM


I noted with great interest the live reports, last week, by Liz Adler from the Zinc Signals 2007 meeting. Those interested in zinc biology maybe interested to hear that the newly constituted Society for Zinc Biologywill be hosting its first international meeting, which is open to all,from 10-14 Feb, 2008 in Banff, Canada (

Society for Zinc Biology

Jun 14 2007 8:13AM


After the great success of the 2006 Zinc Signals Meeting, we decided that the time was ripe to establish an International Society for Zinc Biology (SZB), and to hold a biannual meeting that could bring together all the scientists working in the many biological fields in which Zn2+ is involved.

The SZB ( was established in February 2007. We list already 100+ distinguished members, and we are definitely looking for the first SZB meeting to be held in Banff (from 10-14 Feb, 2008) torecruit many new researchers, as well as to vote for our SZB Advisory Board.

The meeting is set to offer a public arena for top notch scientific debate and open discussion of latest findings and controversies that are animating the field.

Come and have great fun in Banff. There will be more than what you ZinK!

Stefano Sensi, MD PhD

Past Co-Chair of the 2006 Zinc Signals Meeting

Founding of the International Society for Zinc Biology

Aug 20 2008 9:11AM

Glen K. Andrews

We are delighted to announce the founding of the InternationalSociety for Zinc Biology (ISZB). Zinc is well known to biologists for its roles as an essential cofactor for many enzymes active in digestion andmetabolism, and in transcription factors active in the control of geneexpression. It has become increasingly appreciated that zincalso plays critical roles in the nervous, reproductive, and immune systems, as well as in embryonic development. Evidence is accumulating that zinchas important functions in regulating signal transduction cascades in thecell and may be involved in several diseases, including Alzheimer disease, diabetes, stroke, cancer, wound healing, and macular degeneration of theeye. The Society is an international, nonprofit organization; one of ourgoals is to bring together scientists from a diversity of fieldsthat have a common interest in the structural, biochemical, genetic andphysiological aspects of zinc biology. Membership is open to individualsfrom any nation, including scientists, students, physicians, regulators,sponsors, and any other professionals interested in zinc biology. Further details and information on future meetings, current members, and how tojoin the Society can be found on our website:

For further information contact Professor Glen K. Andrews, President of the Society, or contact us via the E-mail address of the society