Bouvier, Muriel; (1993) Stoichiometry and transport properties of the glutamate uptake carrier in salamander Muller cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glutamate is a major neurotransmitter in the central nervous system (CNS). The synaptic action of neurotransmitter glutamate is ultimately terminated by its uptake into glial cells and neurones. Uptake of glutamate is also important because it maintains the extracellular glutamate concentration below neurotoxic levels. Some of the sulphur-containing analogues of glutamate are also thought to have a possible role as neurotransmitters in the CNS and some of them may accumulate extracellularly and cause neuronal death. The uptake of glutamate, aspartate and of their sulphur-containing analogues was studied in salamander retinal glial cells, using the whole-cell configuration of the patch-clamp technique. Sulphur-containing analogues of glutamate and aspartate were shown to be transported on the glutamate uptake carrier with different affinities. The low affinity for transport of some of the analogues might explain their neurotoxic effect. The possible transport of a pH-changing ion on the glutamate uptake carrier was investigated. Glutamate uptake was shown to be accompanied by an intracellular acidification and an intracellular alkalinization. These pH changes have the sodium-and potassium-dependence and the pharmacology of glutamate uptake. They were shown not to be due to metabolism nor to secondary activation of pH-regulating mechanisms. The effect of certain anions inside the cell on the amplitude of the current evoked by glutamate uptake was investigated. This approach was used to show that the pH changes described above were due to an anion such as hydroxyl or bicarbonate being transported out on the glutamate uptake carrier, rather than due to a proton being transported into the cell. Anion-sensitive electrodes provided direct evidence for the transport of anions out of the cell on the glutamate uptake carrier. The possible modulatory effects of various agents such as ATP, adenosine, ascorbate and annexin I were tested on the magnitude of the current evoked by the transport of glutamate. The effect of activating or inhibiting protein kinases was also studied.

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