Zinc-mediated feedback at the synaptic terminals of vertebrate photoreceptors

Abstract

There is mounting evidence that zinc release from glutamatergic nerve terminals serves as a neuromodulator at synaptic sites within the retina and CNS. However, it has not been possible to reliably measure the concentration of zinc co-released with glutamate in the confines of the synaptic cleft. Thus, much of the evidence supporting this view derives from electrophysiological studies showing the modulatory effects of exogenous zinc on the membrane currents of ligand-and voltagegated channels. In the present study, we took advantage of the unique properties of the glutamatergic photoreceptor terminal to demonstrate a feedback signal mediated by endogenous zinc at the synaptic sites from which it is discharged. Through its ability to block voltage-gated calcium channels in the photoreceptor terminal, zinc suppresses the radial dark current of the visual cell, and reduces its release of glutamate. It follows that chelation of extracellular zinc, e.g., with histidine, will lead to an increase both in the dark current and in the release of glutamate, changes that result in an enhancement of the light-evoked a-wave of the ERG and can account for the b-wave enhancement observed previously after zinc chelation when inner retinal responses were not blocked by aspartate. Keywords skate; retina; rod photoreceptors; zinc; feedback Zinc is unquestionably one of the most ubiquitous trace elements in biological systems, and it is now universally acknowledged that zinc is indispensable to all living organisms: (i) zinc serves as an integral and essential component of scores of enzymes, (ii) it participates in a wide variety of metabolic functions, and (iii) it plays a significant role in translation and transcription of the genetic message. Moreover, zinc is indispensable to the growth and development of all forms of life (cf. reviews by Vallee, 1988;O'Halloran, 1993), and the serious consequences of zinc deficiency have been well documented (cf. Smith et al., 1973;Leopold, 1978;Hambidge, 1981;Krebs et al., 2000;Di Cello et al., 2005;Olmez et al., 2007). With the advent of a range of sensitive detection methods (cf. Danscher et al., 1985;Frederickson et Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1982, 1987Christensen et al., 1992;Simons, 1993;Thompson et al., 2002), zinc was shown to be present in virtually every tissue of the body where it exists primarily complexed with proteins that serve both metabolic reactions and structural functions. Although there is evidence for the presence of free or loosely bound Zn 2+ ions within the cytoplasm and body fluids (Frederickson, ...

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