Billups, Brian James; (1997) Properties of glutamate uptake in glial cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glutamate uptake carriers are ultimately responsible for terminating the synaptic action of glutamate by sequestering it into neurons and glia. Glutamate transport is accompanied by the co-transport of two sodium ions and the countertransport of one potassium and one hydroxide ion, so it is electrogenic, carrying net positive charge inwards with each glutamate anion. The ionic changes occurring in pathological conditions like brain ischaemia cause glutamate uptake carriers to run backwards, pumping glutamate out of cells. Since glutamate uptake involves the movement of a hydroxide ion, and rapid pH changes occur during brain ischaemia, the effects of changing internal and external pH on forward and reversed uptake were studied. Forward and reversed glutamate transport were studied by whole-cell voltage-clamping glial cells (Muller cells) isolated from the salamander retina. Glutamate release by reversed uptake was also monitored using isolated rat cerebellar neurons as glutamate sensors. Internal alkalinization promoted, and external alkalinization inhibited glutamate uptake, probably by altering the gradient for hydroxide counter-transport. External acidification inhibited uptake, by decreasing the carriers' sodium affinity. Glutamate release by reversed uptake was inhibited by external acidification. This may be neuroprotective during anoxia, since the rise in external glutamate concentration is neurotoxic. Cloned mammalian glutamate uptake carriers are known to have an integral anion conductance. This was also shown to be the case for the salamander transporter, and the gating of this conductance was studied. It was activated by either forward or reversed glutamate uptake. Furthermore, cycling of the carrier was not an absolute requirement for channel opening. When cycling was inhibited, binding of glutamate and sodium to the internal and external carrier surface was sufficient to activate the anion conductance. Anion flow through the conductance was shown not to be coupled to glutamate transport, while the movement of hydroxide on the transporter is coupled to glutamate transport.

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