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Is Zinc a Neuromodulator?
Alan R. Kay and Katalin Tóth (13 May 2008)
Sci. Signal. 1 (19), re3-re3. [DOI: 10.1126/stke.119re3]
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Zinc Release at the Synaptic Terminals

The review by Kay and Tóth (1) ignores a body of evidence that shows the release of synaptic zinc by stimulation of mossy fibers. The authors make the claim “This zinc-release hypothesis has, however, proved difficult to confirm.” They claim further that zinc release upon stimulation and blockade by antagonist are stumbling blocks in the case for zinc as a modulator. While I agree that the experiments are difficult, many of the reasons for failures to detect released zinc were discussed by Frederickson et al. (2) who provided explanations for why synaptic zinc release was not detected in some experimental systems and why the detected concentrations of released zinc were depressed under particular experimental conditions. Furthermore, there is a substantial body of evidence using various experimental systems that are optimized for detection of released zinc that convincingly support the zinc-release hypothesis (2-11). There are also numerous papers showing that chelation of intrinsic zinc signals changes neuronal function in a manner opposite to the changes produced by adding exogenous zinc. Thus, in my opinion, there is ample evidence for zinc as a synaptically released neuromodulator.


  1. A. R. Kay, K. Tóth, Is zinc a neuromodulator? Sci. Signal. 1, re3 (2008). [Abstract] [Full Text]
  2. C. J. Frederickson, L. I. Giblin 3rd, R. V. Balaji, R. Masalha, C. K. Frederickson, Y. Zeng, E. V. Lopez , J. Y. Koh, U. Chorin, L. Besser, M. Hershfinkel, Y. Li, R. B. Thompson, A. Krezel, Synaptic release of zinc from brain slices: factors governing release, imaging, and accurate calculation of concentration. J. Neurosci. Methods 154, 19-29 (2006). [PubMed]
  3. C. Bastian, Y. V. Li, Fluorescence imaging study of extracellular zinc at the hippocampal mossy fiber synapse. Neurosci. Lett. 419, 119-124 (2007). [PubMed]
  4. J. Qian, J. L. Noebels, Visualization of transmitter release with zinc fluorescence detection at the mouse hippocampal mossy fibre synapse. J. Physiol, 566, 747-758 (2005). [Abstract] [Full Text]
  5. K. Komatsu, K. Kikuchi, H. Kojima, Y. Urano,T. Nagano, Selective zinc sensor molecules with various affinities for Zn2+, revealing dynamics and regional distribution of synaptically released Zn2+ in hippocampal slices. J. Am. Chem. Soc. 127, 10197-10204 (2005). [PubMed]
  6. R. B. Thompson, W. O. Whetsell Jr., B. P. Maliwal, C. A. Fierke, C. J. Frederickson, Fluorescence microscopy of stimulated Zn(II) release from organotypic cultures of mammalian hippocampus using a carbonic anhydrase-based biosensor system. J Neurosci. Methods 96, 35-45 (2000). [PubMed]
  7. Y. Li, C. J. Hough, C. J. Frederickson, J. M. Sarvey, Induction of mossy fiber --> Ca3 long-term potentiation requires translocation of synaptically released Zn2+. J. Neurosci 21, 8015-8025 (2001). [Abstract] [Full Text]
  8. J. K. Ketterman, Y. V. Li, Presynaptic evidence for zinc release at the mossy fiber synapse of rat hippocampus. J. Neurosci. Res. 86, 422-434 (2008). [PubMed]
  9. S. Ueno, M. Tsukamoto, T. Hirano, K. Kikuchi, M. K. Yamada, N. Nishiyama, T. Nagano, N. Matsuki, Y. Ikegaya, Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits. J. Cell. Biol. 158, 215-220 (2002). [Abstract] [Full Text]
  10. Y. Li, C. J. Hough, S. W. Suh, J. M. Sarvey, C. J. Frederickson, Rapid translocation of Zn2+ from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J. Neurophysiol. 86, 2597-2604 (2001). [Abstract] [Full Text]
  11. S. Redenti, H. Ripps, R. L. Chappell, Zinc release at the synaptic terminals of rod photoreceptors. Exp. Eye Res. 85, 580-584 (2007). [PubMed]

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