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-clam p technique. In the pH range of 5.0-9.0, increased extracellular pH en hanced, and decreased extracellular pH suppressed, current activated b y 10 mu M 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 GABA(A)-selective agonist muscimol in all n eurons tested. The antagonism of GABA-activated current by lowering th e pH was equivalent at holding potentials between -80 and +40 mV and d id not involve a significant alteration in reversal potential. Acidifi cation shifted the GABA concentration/response curve to the right, sig nificantly increasing the EC50 for GABA without appreciably changing t he slope or maximal value of the curve. Inhibition of the GABA-activat ed current by protons was not significantly differ ent when the patch- pipette solution was buffered at pH 7.4 or pH 6.5. These results sugge st that extracellular protons inhibit GABA(A) receptor channels in pri mary sensory neurons by decreasing the apparent affinity of the recept or for GABA. This represents a novel mechanism of inhibition by proton s of a neurotransmitter-gated ion channel. Proton inhibition of GABA(A ) receptor channels may account in part for the modulation by protons of sensory information transmission under certain pathophysiological c onditions.