Pharmacological evidence for the concept of spare glutamate transporters
(2021) Neurochemistry International : the journal for the publication of cellular and molecular aspects of neurochemistry — Vol. 149, p. 105142 (2021)
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- Authors
Damblon, Jonathan 
Ingelbrecht, Caroline
- Abstract
- Through the efficient clearance of extracellular glutamate, high affinity astrocytic glutamate transporters constantly shape excitatory neurotransmission in terms of duration and spreading. Even though the glutamate transporter GLT-1 (also known as EAAT2/SLC1A2) is amongst the most abundant proteins in the mammalian brain, its density and activity are tightly regulated. In order to study the influence of changes in the expression of GLT-1 on glutamate uptake capacity, we have developed a model in HEK cells where the density of the transporter can be manipulated thanks to a tetracycline-inducible promoter. Exposing the cells to doxycycline concentration-dependently increased GLT-1 expression and substrate uptake velocity. However, beyond a certain level of induction, increasing the density of transporters at the cell surface failed to increase the maximal uptake. This suggested the progressive generation of a pool of spare transporters, a hypothesis that was further validated using the selective GLT-1 blocker WAY-213613 of which potency was influenced by the density of the transporters. The curve showing inhibition of uptake by increasing concentrations of WAY-213613 was indeed progressively rightward shifted when tested in cells where the transporter density was robustly induced. As largely documented in the context of cell-surface receptors, the existence of ‘spare’ glutamate transporters in the nervous tissue and particularly in astrocytes could impact on the consequences of physiological or pathological regulation of these transporters.
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Citations
Belo Do Nascimento Osorio De Castro, I., Damblon, J., Ingelbrecht, C., Goursaud, S., Massart, M., Dumont, A., Desmet, N., & Hermans, E. (2021). Pharmacological evidence for the concept of spare glutamate transporters. Neurochemistry International : the journal for the publication of cellular and molecular aspects of neurochemistry, 149, 105142. https://doi.org/10.1016/j.neuint.2021.105142 (Original work published 2021)