Proton inhibition of GABA-activated current in rat primary sensory neurons.

The modulation of the Cl- current activated by gamma-aminobutyric acid (GABA) by changes in extracellular pH in freshly isolated rat dorsal root ganglia (DRG) neurons was studied using the whole-cell patch-clamp technique. In the pH range of 5.0-9.0, increased extracellular pH enhanced, and decreased extracellular pH suppressed, current activated by 10 microM GABA in a reversible and concentration-dependent manner with an IC50 of pH 7.1 in these neurons. Acidification to pH 6.5 inhibited currents activated by the GABAA-selective agonist muscimol in all neurons tested. The antagonism of GABA-activated current by lowering the pH was equivalent at holding potentials between -80 and +40 mV and did not involve a significant alteration in reversal potential. Acidification shifted the GABA concentration/response curve to the right, significantly increasing the EC50 for GABA without appreciably changing the slope or maximal value of the curve. Inhibition of the GABA-activated current by protons was not significantly different when the patch-pipette solution was buffered at pH 7.4 or pH 6.5. These results suggest that extracellular protons inhibit GABAA receptor channels in primary sensory neurons by decreasing the apparent affinity of the receptor for GABA. This represents a novel mechanism of inhibition by protons of a neurotransmitter-gated ion channel. Proton inhibition of GABAA receptor channels may account in part for the modulation by protons of sensory information transmission under certain pathophysiological conditions.