Modulation of non-vesicular glutamate release by pH.

Glutamate uptake into glial cells helps to keep the brain extracellular glutamate concentration, [glu]o, below levels that kill neurons. Uptake is powered by the transmembrane gradients of Na+, K+ and pH. When the extracellular [K+] rises in brain ischaemia, uptake reverses, releasing glutamate into the extracellular space. Here we show, by monitoring glutamate transport electrically and detecting released glutamate with ion channels in neurons placed outside glial cells, that a raised [H+] inhibits both forward and reversed glutamate uptake. No electroneutral reversed uptake was detected, contradicting the idea that forward and reversed uptake differ fundamentally. Suppression of reversed uptake by the low pH occurring in ischaemia will slow the Ca(2+)-independent release of glutamate with can raise [glu]o to a neurotoxic level, and will thus protect the brain during a transient loss of blood supply.