| Physiological signalling mediated by changes in cytoplasmic pH has been documented in a wide variety of cell types. Often, growth factor or classical hormone receptors are coupled to the activation of H+ transport, resulting in pH shifts over minutes to hours. In the nervous system, however, electrical signalling takes place in milliseconds to seconds. Recently, mechanisms have been discovered which can modulate pH on an equally rapid time scale. In the brain, the pH shifts associated with electrical activity are regionally specific, and go through developmental changes that parallel the maturation of the neuroglia. The focus of this laboratory has been to elucidate the mechanisms which rapidly transport acid during neuronal activity, to establish the role of the neuroglia in brain pH regulation, and to determine how H+ may serve as an intracellular and extracellular signal in brain function. We have established that neural activity triggers a rapid loss of H+ from the extracellular space. This is particularly evident in the hippocampus, where excitatory synaptic input can give rise to a rise in extracellular pH in a few milliseconds. Because the NMDA receptor- and voltage-dependent Ca2+ channels are sensitive to external H+, we are particularly interested in how these pH shifts modify neuronal excitability and synaptic transmission. Glial cells express one or more voltage-dependent H+ transporters in the plasma membrane. Consequently, these cells undergo a rapid increase in intracellular pH during neuronal activity. It has been proposed that these pH shifts are the signals which link rapid glial metabolic responses and neuronal activity. The H+ transport systems of the glia, and their physiological role, are the second major focus of this laboratory.
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