Modulation of non-vesicular glutamate release by pH

Abstract

GLUTAMATE uptake into glial cells helps to keep the brain extracellular glutamate concentration, [glu]₀, below levels that kill neurons. Uptake is powered^1–4 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^5,6. 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 idea⁷ that forward and reversed uptake differ fundamentally. Suppression of reversed uptake by the low pH occurring in ischaemia^8,9 will slow the Ca²⁺-independent release of glutamate¹⁰ which can raise [glu]₀ to a neurotoxic level ^11,12, and will thus protect the brain during a transient loss of blood supply.