The role of glutamate and glutamine metabolism and related transporters in nerve cells

Abstract

Background: Glutamate and glutamine are the most abundant amino acids in the blood and play a crucial role in cell survival in the nervous system. Various transporters found in cell and mitochondrial membranes, such as the solute carriers (SLCs) superfamily, are responsible for maintaining the balance of glutamate and glutamine in the synaptic cleft and within cells. This balance affects the metabolism of glutamate and glutamine as non-essential amino acids.

Aims: This review aims to provide an overview of the transporters and enzymes associated with glutamate and glutamine in neuronal cells.

Discussion: We delve into the function of glutamate and glutamine in the nervous system by discussing the transporters involved in the glutamate-glutamine cycle and the key enzymes responsible for their mutual conversion. Additionally, we highlight the role of glutamate and glutamine as carbon and nitrogen donors, as well as their significance as precursors for the synthesis of reduced glutathione (GSH).

Conclusion: Glutamate and glutamine play a crucial role in the brain due to their special effects. It is essential to focus on understanding glutamate and glutamine metabolism to comprehend the physiological behavior of nerve cells and to treat nervous system disorders and cancer.

Keywords: glutamate metabolism; glutamate transporters; glutamine metabolism; glutamine transporters; nerve cells.

FIGURE 1

Glutamate–glutamine cycle in nerve cells. Glutamate (Glu) is transported into synaptic vesicles through VGLUTs, and glutamatergic neurons release glutamate to synapses through synaptic vesicles. The postsynaptic glutamate receptors are activated by glutamate, inducing synaptic signal transmission. Most of the glutamate in synapses is transported into astrocytes by GLT and/or GLSAT and converted into glutamine (Gln) in cells by GS. Glutamine in astrocytes is then secreted into synapses through SNAT3, SNAT5, and/or HM. Glutamine is retaken through SNAT1 and/or SNAT2 by neurons, where it is converted into glutamate by GLS.

FIGURE 2

Intracellular metabolism of glutamate and glutamine. In the cytoplasm, glutamate (Glu) generates alanine (Ala) and phosphoserine (pSer) by deamination of glutamate pyruvate transaminase and phosphoserine aminotransferase, respectively. pSer further generates glycine by serine hydroxymethyltransferase. Glutamate, cysteine, and glycine combine to form reduced glutathione (GSH), which helps maintain the content of GPX4 in cells and protects cells from lipid peroxidation. Glutamate is transported into the mitochondria via the GC1 and AGC1 transporters, with the latter closely related to the aspartate–malate shuttle system. The pathway by which glutamine (Gln) enters the mitochondria is not well understood as of now. In mitochondria, glutamate participates in the TCA cycle through the deamination of glutamate dehydrogenase (GLUD) to α‐KG. α‐KG can also generate citrate through the reductive carboxylation (RC) pathway, which is involved in de novo synthesis of fatty acids.