Proton-gated ion channels in cultured mouse cortical neurons were characterized using the patch clamp technique. In voltage clamp, rapid shifts of the extracellular saline from pH 7.4 to < 7.0 invariably triggered inward currents carried by sodium. The currents were inhibited by Amiloride (IC50: 6.2 microM). In current clamp, acidic saline depolarized the neurons and triggered trains of action potentials. Concentration-response experiments revealed an extreme intercell variance as the EC50-value for protons varied from pH 6.8 to 5.6, indicating heterogeneity in channel type expression from cell to cell. The possible involvement of acid sensing ion channels in ischemic neurodegeneration is discussed.