Extracellular glutamate regulates the abundance of glutamate receptors via xCT-like transporters

Glutamate receptors are ligand-gated ion channels that play an important role in both mammalian and invertebrate central and peripheral synapses. I investigated the role ambient glutamate has in regulating glutamate receptors abundance, and indirectly, the strength of synaptic neurotransmission.;My results show that: (1) extracellular glutamate acts as a negative regulator of glutamate receptor field density in the larval neuromuscular junction, through a mechanism that requires the binding of glutamate to receptors themselves, as well as receptor desensitization, (2) a putative Drosophila transporter named Genderblind (GB) is critical for the regulation of ambient glutamate concentration in vivo, most likely through an antiport mechanism in which intracellular glutamate is exchanged for extracellular cystine, and (3) JhI-21, another putative Drosophila cystine-glutamate transporter-encoding gene, also acts as a negative regulator of the abundance of synaptic glutamate receptors. It is likely that JhI-21 acts through a similar mechanism as GB, i.e. by regulating the concentration of extracellular glutamate.;These findings reveal a novel mechanism for regulation of glutamate receptor localization and propose a new role for cystine-glutamate antiporters.