Is zinc a neuromodulator?

Abstract

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.

Fig. 1

Chelators. Membrane-impermeant chelators are in black and membrane-permeant ones are in blue.

Fig. 2

Phasic (A) versus tonic (B) zinc release. Zinc ions are shown as red spheres. In the tonic mode zinc ions are bound to membrane associated macromolecules (not shown) in synaptic vesicles and on the pre- and postsynaptic membrane.

Fig. 3

Chelation removes zinc inhibition of the mossy fiber NMDA synaptic response. (A) CA3 pyramidal cell indicating approximate position of the stratum lucidum (sl; MF pathway) and stratum radiatum (sr; AC pathway). The CA3 neuron [from (56)] was obtained from the “Hippocampal neuronal morphology site” (www.compneuro.org/CDROM/nmorph/cellArchive.html). (B) (Top) Synaptic currents elicited under voltage-clamp (holding potential −40 mV) in a CA3 pyramidal cell on stimulation of the mossy fiber pathway in the presence of 0.5 mM Mg²⁺, 12 μM NBQX, and 100 μM picrotoxin, in the presence and absence of Ca-EDTA. (Bottom) Response of the same cell to stimulation of the AC pathway. (C) Effect of the application of 2.5 mM Ca-EDTA on the synaptic currents elicited by MF (❍) or AC stimulation (●); (mean ±SEM, n = 6). The horizontal bar represents the duration of the Ca-EDTA application. [Modified from (38), with permission from Elsevier]