Evidence that Zn²⁺ chelation potentiates the currents mediated by either homomeric ASIC1a or heteromeric ASIC1a-ASIC2a channels in native neurons and dose-dependent inhibition of ASIC current in cortical neurons by buffered free Zn²⁺ at nanomolar concentrations. A, B, Representative traces and summary data showing TPEN potentiation of ASIC current that is likely carried by heteromeric ASIC1a-ASIC2a channels in cortical neurons. Currents in these neurons are activated by moderate pH decrease and potentiated by 100 μm Zn²⁺, consistent with the presence of ASIC1a-ASIC2a channels. C, D, Representative traces and summary data showing TPEN potentiation of ASIC current that is likely carried by homomeric ASIC1a channels in cortical neurons. Currents in these neurons are activated by a moderate decrease of pH but are insensitive to 100 μm Zn²⁺, consistent with the presence of homomeric ASIC1a channels. E, F, ASIC currents in acutely dissociated mature neurons are also potentiated by Zn²⁺ chelation. G, Representative traces demonstrating concentration-dependent inhibition of the ASIC current in cultured mouse cortical neurons by different concentrations of free Zn²⁺. ASIC currents were activated by pH reduction from 7.4 to 6.5 at a holding potential of -60 mV. H, Summary of Zn²⁺ dose-inhibition relationship from six neurons with an average IC₅₀ value of 14.2 ± 0.36 nm and a Hill coefficient of 0.86 ± 0.01. The inhibition of ASIC currents by Zn²⁺ is partial, with ∼30% residual current left at a concentration of Zn²⁺ >300 nm. ^*p < 0.05; ^**p < 0.01.