Suppression by zinc of AMPA receptor-mediated synaptic transmission in the retina.
Zinc is strikingly co-localized with glutamate-containing vesicles in the synaptic terminals of retinal photoreceptors, and it is thought to be co-released with glutamate onto postsynaptic neurons such as horizontal cells and bipolar cells. Here we examined exogenous zinc modulation of glutamate receptors on cultured retinal horizontal cells using patch-clamp recording and endogenous zinc effect on intact horizontal cells using intracellular recording techniques. Application of 3, 30, and 300 microM zinc reduced the whole cell peak current of response to 200 microM glutamate by 2, 30, and 56%, respectively. Zinc suppression of glutamate response persisted in the presence of 10 microM cyclothiazide (CTZ). Glutamate responses of outside-out patches were completely abolished by 30 microM 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), and the receptor desensitization was blocked by 30 microM CTZ, indicating that receptor target for the zinc action on horizontal cells is alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid (AMPA) receptors. Zinc decreased the amplitude of outside-out patch peak current without an effect on either its 10-90% rise time or the rate of receptor desensitization. Dose-response curves for glutamate show that zinc reduced the maximal current evoked by glutamate and increased EC(50) from 50 +/- 3 to 70 +/- 6 microM without changing the Hill coefficient. Chelation of endogenous zinc with 1 mM Ca-EDTA depolarized horizontal cells in the intact retina by 3 mV, consistent with relief of the partial glutamate receptor inhibition by zinc. Overall, the results describe a unimodal form of zinc modulation of AMPA-type glutamate receptor responses not previously described in native neuronal preparations and a novel role for endogenous zinc in modulating neurotransmission.
Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0084, USA.
Dao-Qi
DQ
Zhang
Christophe
C
Ribelayga
Stuart C
SC
Mangel
Douglas G
DG
McMahon
D000818:Animals; D001492:Bass; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007700:Kinetics; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology*
D002614:Chelating Agents; D018091:Receptors, AMPA; D018698:Glutamic Acid; D004492:Edetic Acid; D015032:Zinc