Modulation of neuronal function by intracellular pH

Recent studies have revealed that excitation of specific nerve pathways can produce localized changes of pH in nervous tissue. It is important to determine both how these pH changes are generated and, even more importantly, how the excitability of neurons in the localized areas are affected. Evidence indicates that activation of both gamma-aminobutyric acid (GABA) and L-glutamate receptor channels in inhibitory and excitatory pathways, respectively, can raise extracellular pH (pH(o)) and lower intracellular pH (pH(i)). At the target location, it has been shown that several types of voltage-gated ion channels in neurons were modified by a change in pH(i). These studies, taken together, enable us to hypothesize that intracellular hydrogen ions (H+) might function as neuromodulatory factors, like other types of intracellular second messengers. This hypothesis was tested by using horizontal cells enzymatically dissociated from catfish retina. We found that the high-voltage-activated (HVA) Ca2+ current, inward rectifier K+ current and hemi-gap junctional current are modulated by a change in intracellular H+ concentration, and that L-glutamate suppresses the HVA Ca2+ current by raising the intracellular H+ concentration. These observations support the hypothesis that intracellular H+, acting as a second messenger, governs neuronal excitability via modulation of ionic channel activity. This article reviews recent studies of ours and others on the effect of pH, upon neuronal function.