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The Glutamine Transporters and Their Role in the Glutamate/GABA–Glutamine Cycle

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The Glutamate/GABA-Glutamine Cycle

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 13))

Abstract

Glutamine is a key amino acid in the CNS, playing an important role in the glutamate/GABA–glutamine cycle (GGC). In the GGC, glutamine is transferred from astrocytes to neurons, where it will replenish the inhibitory and excitatory neurotransmitter pools. Different transporters participate in this neural communication, i.e., the transporters responsible for glutamine efflux from astrocytes and influx into the neurons, such as the members of the SNAT, LAT, y+LAT, and ASC families of transporters. The SNAT family consists of the transporter isoforms SNAT3 and SNAT5 that are related to efflux from the astrocytic compartment, and SNAT1 and SNAT2 that are associated with glutamine uptake into the neuronal compartment. The isoforms SNAT7 and SNAT8 do not have their role completely understood, but they likely also participate in the GGC. The isoforms LAT2 and y+LAT2 facilitate the exchange of neutral amino acids and cationic amino acids (y+LAT2 isoform) and have been associated with glutamine efflux from astrocytes. ASCT2 is a Na+-dependent antiporter, the participation of which in the GGC also remains to be better characterized. All these isoforms are tightly regulated by transcriptional and translational mechanisms, which are induced by several determinants such as amino acid deprivation, hormones, pH, and the activity of different signaling pathways. Dysfunctional glutamine transporter activity has been associated with the pathophysiological mechanisms of certain neurologic diseases, such as Hepatic Encephalopathy and Manganism. However, there might also be other neuropathological conditions associated with an altered GGC, in which glutamine transporters are dysfunctional. Hence, it appears to be of critical importance that the physiological and pathological aspects of glutamine transporters are thoroughly investigated.

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Abbreviations

AAR:

Amino acid response

AARE:

AAR elements

APC:

Amino acid- polyamine- and organocations family

BCH:

2-Aminobicyclo-(2-2-1)-hepatane-2-caboxylic acid

CATs:

Cationic amino acid transporters

CNS:

Central nervous system

DHT:

Dihydrotestosterone

EAAT:

Excitatory amino acid transporters

EGFR:

Epidermal growth factor receptor

eIF2α:

Eukaryotic initiation factor 2α

ERK:

Extracellular regulated kinase

FXR:

Farnesoid X receptor

GABA:

Gamma-aminobutyric acid

GAT:

Gamma-aminobutyric acid transporter

GGC:

Glutamate/GABA–glutamine cycle

GS:

Glutamine synthetase

HATs:

Heteromeric amino acid transporters

HE:

Hepatic encephalopathy

IPSC:

Inhibitory postsynaptic potential

LATs:

L-type amino acid transporters

L-DOPA:

Dihydroxyphenylalanine

MAP2:

Anti-micro-tubule-associated protein-2

MAPK:

Mitogen-activated protein kinase

MeAIB:

α-Methylamino-iso-butyric acid

Mn:

Manganese

PAG:

Phosphate-activated glutaminase

PI3K:

Phosphatidylinositol 3-kinase

PKB:

Protein kinase B

PMA:

Phorbol-12-myristate-13-acetate

SGK:

Glucocorticoid inducible kinase

SNAT:

Solute neutral amino acid transporters

TCA:

Tricarboxylic acid

TMB:

Transmembrane domain

UTR:

3′-untranslated region

vGAT:

Vesicular gamma-aminobutyric acid transporter

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  1. Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, 40530, Sweden

    Renata Leke

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark

    Arne Schousboe

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  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

  2. Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Ursula Sonnewald

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Leke, R., Schousboe, A. (2016). The Glutamine Transporters and Their Role in the Glutamate/GABA–Glutamine Cycle. In: Schousboe, A., Sonnewald, U. (eds) The Glutamate/GABA-Glutamine Cycle. Advances in Neurobiology, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-45096-4_8

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