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R. L. Chappell, I. Anastassov, P. Lugo, H. Ripps; Feedback by Endogenous Zinc Inhibits Glutamate Release at the Synaptic Terminals of Vertebrate Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2208. doi: https://doi.org/.
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The presence of labile ("chelatable") zinc within synaptic vesicles of glutamatergic nerve terminals throughout the retina and CNS led to the suggestion that zinc serves as a neuromodulator at synaptic sites in these regions. Much of the evidence supporting this view derives from electrophysiological studies showing modulatory effects of exogenous zinc on membrane currents of ligand- and voltage-gated 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.
ERG responses were elicited from dark-adapted skate eyecups resting on a chlorided silver disk reference electrode using a chlorided silver wire in contact with the vitreal surface and connected to a high-gain DC-coupled amplifier. Responses were recorded using pClamp and analyzed using Microcal Origin. Oxygenated control Ringer or test solutions were superfused across the eyecup continuously.
The ERG a-wave was recorded from the skate retina after applying 75 mM aspartate to block glutamate-gated channels on post-synaptic horizontal and bipolar cells. Using a saturating flash intensity (1.23 µW/cm2) as control, we show that addition of 100 µM histidine, a zinc-chelating agent, produced a further enhancement of the a-wave potential. At all test intensities, zinc chelation produced significant increases in the photoreceptor response. These data provide good evidence that release of endogenous zinc from the glutamatergic photoreceptor terminal serves as a feedback signal to influence the discharge of neurotransmitter. To demonstrate the specificity of the histidine effect, we found that histidine (100 µM) alone enhanced the averaged isolated a-wave response by more than 50 %, and that when zinc (50 µM) was added to the aspartate Ringer solution, this receptor potential was reduced by 25 %. However, the addition of histidine to the zinc-containing solution significantly reduced the effect of the applied zinc.
The present results indicate that endogenous zinc, co-released with glutamate at pre-synaptic sites within the dark-adapted retina, forms a negative feedback loop capable of suppressing the voltage-dependent calcium current in the receptor terminal. The resultant reduction in vesicular release is reversed by the zinc chelator histidine which leads, in turn, to a significant enhancement of the photoreceptor potential (the ERG a-wave).
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