Is Zinc a Neuromodulator?

Sci. Signal., 13 May 2008
Vol. 1, Issue 19, p. re3
DOI: 10.1126/stke.119re3

Is Zinc a Neuromodulator?

  1. Alan R. Kay1,* and
  2. Katalin Tóth2
  1. 1Department of Biology, 336 BB, University of Iowa, Iowa City, IA 52242, USA.
  2. 2Centre de Recherche and Department of Psychiatry, Université Laval Robert Giffard, 2601 chemin de la Canardière, F6550, Québec, QC G1J 2G3, Canada.
  1. *Corresponding author. E-mail, alan-kay{at}


The vesicles of certain glutamatergic terminals in the mammalian forebrain are replete with ionic zinc. It is believed that during synaptic transmission zinc is released, binds to receptors on the pre- or postsynaptic membranes, and hence acts as a neuromodulator. Although exogenous zinc modulates a wide variety of channels, whether synaptic zinc transits across the synaptic cleft and alters the response of channels has been difficult to establish. We will review the evidence for zinc as a neuromodulator and propose diagnostic criteria for establishing whether it is indeed one. Moreover, we will delineate alternative ways in which zinc might act at synapses.


A. R. Kay and K. Tóth, Is Zinc a Neuromodulator?. Sci. Signal. 1, re3 (2008).

Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc
C. T. Anderson, R. J. Radford, M. L. Zastrow, D. Y. Zhang, U.-P. Apfel, S. J. Lippard, and T. Tzounopoulos
Proc. Natl. Acad. Sci. USA 112, E2705-E2714 (19 May 2015)

Synaptic Zn2+ Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis
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The Intronic GABRG2 Mutation, IVS6+2T->G, Associated with Childhood Absence Epilepsy Altered Subunit mRNA Intron Splicing, Activated Nonsense-Mediated Decay, and Produced a Stable Truncated {gamma}2 Subunit
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The Neurophysiology and Pathology of Brain Zinc
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J. Neurosci. 31, 16076-16085 (9 November 2011)

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