Glutamate-Glutamine metabolism and transport, implications in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative condition caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the formation of Lewy bodies due to α-Synuclein (α-Syn) aggregation in the midbrain. Glutamate (Glu) is an excitatory neurotransmitter that plays an important role in the normal functioning of the basal ganglia circuit. It has been shown recently that Glu receptors are involved in the regulation of neurotransmitter release, neuron excitability and long-term plasticity and the altered mechanisms in Parkinson's disease. Glu is produced in the cytoplasm and is packed and stored in vesicles by vesicular glutamate transporters (VGLUTs). Following its release into the synaptic cleft, it exerts its physiological effects by binding to ligand-gated ion channels (ionotropic glutamate receptors (iGluRs)) and G-protein coupled receptors (metabotropic glutamate receptors (mGluRs)). Lack of glutamate reuptake or enzymatic decomposition results in Glu accumulation at the synapse, causing excitotoxicity. This is prevented by excitatory amino acid transporters (EAATs), which reabsorb the extracellular Glu. Furthermore, elevated extracellular glutamate levels prevent cystine uptake, which results in oxidative glutamate toxicity and glutathione depletion. Currently, there are no effective treatments for Parkinson's disease, as most of the drugs that exist have greater side effects, like dyskinesia. Hence, the identification of new potential drug targets is an important factor for improving the therapeutic strategies to combat the disease. Therefore, in this review, we aim to discuss about characteristics of these receptors and transporters and highlight the neuroprotective effects and pharmacological manifestations in Parkinson's disease.