FIG. 16.
Glutamate released by system xc− modulates synaptic activity. Glutamate released into the synaptic cleft is taken up by astrocytic glutamate transporters (EAAT) Extrasynaptically, glutamate released by system xc− activates presynaptic metabotropic glutamate receptors 2 and 3 (mGluR2/3) and thereby reduces the release probability of vesicular glutamate into the synaptic cleft. Postsynaptically, glutamate released by system xc− activates metabotropic glutamate receptor 5 (mGluR5). As a result, long-term depression (LTD) is permitted. The cyst(e)ine pro-drug N-acetyl cysteine can increase extracellular cystine, thereby activating glutamate release by system xc− and subsequently increasing signaling through pre- and postsynaptic mGluRs.