The Na(+)/H(+) exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons.

The effects of pH(i) on GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were studied in mechanically dissociated CA3 pyramidal neurons, by use of ammonium prepulse and whole-cell patch-clamp techniques, under the voltage-clamp condition. NH(4)Cl itself, which is expected to alkalinize pH(i), increased GABAergic mIPSC frequency in a concentration-dependent manner. In contrast, NH(4)Cl decreased mIPSC frequency, either in the presence of 200 microm Cd(2+) or in Ca(2+)-free external solution, suggesting that intraterminal alkalosis decreased GABAergic mIPSC frequency while [NH4(+)] itself may activate Ca(2+) channels by depolarizing the terminal. On the other hand, GABAergic mIPSC frequency was greatly increased immediately after NH(4)Cl removal, a condition expected to acidify pH(i), and recovered to the control level within 2 min after NH(4)Cl removal. This explosive increase in mIPSC frequency observed after NH(4)Cl removal was completely eliminated after depletion of Ca(2+) stores with 1 microm thapsigargin in the Ca(2+)-free external solution, suggesting that acidification increases in intraterminal Ca(2+) concentration via both extracellular Ca(2+) influx and Ca(2+) release from the stores. However, the acidification-induced increase in mIPSC frequency had not recovered by 10 min after NH(4)Cl removal either in the Na(+)-free external solution or in the presence of 10 microm 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), a specific Na(+)/H(+) exchanger (NHE) blocker. The present results suggest that NHEs are major intraterminal pH regulators on GABAergic presynaptic nerve terminals, and that the NHE-mediated regulation of pH(i) under normal physiological or pathological conditions might play an important role in the neuronal excitability by increasing inhibitory tones.