The effect of H+ on the N-methyl-D-aspartate-induced (NMDA) membrane current in enzymatically isolated catfish cone horizontal cells was investigated. Extracellular acidification to pH 5.5 blocked nearly completely the NMDA-induced current and reduced desensitization. The pK for the H+ effect was 6.5, near that for the free amino acid histidine. Protons did not alter the receptor affinity for NMDA and the inhibition was insensitive to the membrane potential and surface charge screening. However, extracellular H+ increased the IC50 for Zn2+. These results indicate that protons can modulate the NMDA-induced membrane current by a mechanism that may include interaction with histidine residues.