Allosteric modulation of native cochlear P2X receptors: insights from comparison with recombinant P2X2 receptors

Extracellular adenosine 5'-triphosphate (ATP)-gated ion channels assembled from P2X receptor subunits exhibit subunit-selective allosteric modulation by protons and divalent cations. In voltage-clamped guinea-pig cochlear outer hair cells (OHC) and Deiters' cells (DC), H(+) and Cu(2+), but not Zn(2+), enhanced the P2X receptor-mediated inward currents. Acid pH (6.5) potentiated OHC ATP-gated currents by 45%. Co-application of Cu(2+) (1-40 microM) with ATP increased the response by 20%. In DCs, ATP-gated currents were potentiated 85% by acid pH, and 70% by Cu(2+). Alkaline pH inhibited ATP-gated inward currents by 73% in OHCs and 85% in DCs. Zn(2+) was either ineffective (1-10 microM) or inhibitory (40-400 microM). Recombinant rat P2X(2) receptor-mediated inward currents in XENOPUS oocytes displayed allosteric modulation that was different from the native guinea-pig cochlear P2X receptors. The oocyte ATP-gated inward current was potentiated 450% by shifting from pH 7.5 to pH 6.5, and 130% with 40 microM Cu(2+). The enhanced response to ATP with acid pH and Cu(2+) is a signature of the P2X(2) subunit. In contrast to native guinea-pig cochlear cells, extracellular Zn(2+) (40 microM) increased the recombinant ATP-gated inward current by 200% in oocytes. These results suggest that the positive allosteric modulation of cochlear OHC and DC ATP-gated ion channels by protons and Cu(2+) arises in part from the P2X(2) receptor subunit, with additional regulatory elements.