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To further analyze the action of copper on brain synaptic mechanisms, the brain dipeptide carnosine (β-alanyl-l-histidine) was tested in Xenopus laevis oocytes expressing the rat P2X[sub 4] or P2X[sub 7] receptors. Ten micromolar copper halved the currents evoked by ATP in both receptors; co-application of carnosine plus copper prevented the metal induced-inhibition with a median effective concentration of 12.1 ± 3.9 and 12.0 ± 5.5 µm for P2X[sub 4] and P2X[sub 7], respectively. Zinc potentiated only the P2X[sub 4] ATP-evoked currents; carnosine had no effect over this metal. The relative potency and selectivity of classical metal chelators to prevent the copper inhibition was compared between carnosine and penicillamine (PA), bathophenanthroline (BPh) or l-histidine (His). Their rank order of potency in P2X[sub 4] and P2X[sub 7] receptors was carnosine = PA = His > BPh > Glycine (Gly) and carnosine = BPh = His > PA > Gly, respectively. The potency to prevent the zinc-induced potentiation in the P2X[sub 4] receptor was BPh > PA > His; carnosine, Gly and β-alanine were inactive. Whereas 1–100 µm carnosine or His alone did not modify the ATP-evoked currents, 10–100 µm PA augmented and 100 µm BPh decreased the ATP-evoked currents. Carnosine was able to revert the copper-induced inhibition restoring the maximal ATP gated current in a concentration-dependent manner. Electronic spectroscopy confirm the formation of carnosine-Cu(II) complexes, mechanism that can account for the prevention and reversal of the copper inhibition, revealing its potential in copper intoxication treatment. [ABSTRACT FROM AUTHOR]