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Glucose, Lactate, β-Hydroxybutyrate, Acetate, GABA, and Succinate as Substrates for Synthesis of Glutamate and GABA in the Glutamine–Glutamate/GABA Cycle

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The Glutamate/GABA-Glutamine Cycle

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

Abstract

The glutamine–glutamate/GABA cycle is an astrocytic-neuronal pathway transferring precursors for transmitter glutamate and GABA from astrocytes to neurons. In addition, the cycle carries released transmitter back to astrocytes, where a minor fraction (~25 %) is degraded (requiring a similar amount of resynthesis) and the remainder returned to the neurons for reuse. The flux in the cycle is intense, amounting to the same value as neuronal glucose utilization rate or 75–80 % of total cortical glucose consumption. This glucose:glutamate ratio is reduced when high amounts of β-hydroxybutyrate are present, but β-hydroxybutyrate can at most replace 60 % of glucose during awake brain function. The cycle is initiated by α-ketoglutarate production in astrocytes and its conversion via glutamate to glutamine which is released. A crucial reaction in the cycle is metabolism of glutamine after its accumulation in neurons. In glutamatergic neurons all generated glutamate enters the mitochondria and its exit to the cytosol occurs in a process resembling the malate-aspartate shuttle and therefore requiring concomitant pyruvate metabolism. In GABAergic neurons one half enters the mitochondria, whereas the other one half is released directly from the cytosol. A revised concept is proposed for the synthesis and metabolism of vesicular and nonvesicular GABA. It includes the well-established neuronal GABA reuptake, its metabolism, and use for resynthesis of vesicular GABA. In contrast, mitochondrial glutamate is by transamination to α-ketoglutarate and subsequent retransamination to releasable glutamate essential for the transaminations occurring during metabolism of accumulated GABA and subsequent resynthesis of vesicular GABA.

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Notes

  1. 1.

    Considerable work has been done studying this mismatch and the larger mismatches that occur during functional activation. There are several theories to explain apparent uncoupling of glucose uptake and oxidation including the astrocyte neuron lactate shuttle (ANLS) , discussed again later, which has received a great deal of attention. As this chapter focuses on oxidative metabolism we refer the reader to two recent reviews on opposite sides of the ANLS controversy (Pellerin and Magistretti 2012; Dienel 2012).

Abbreviations

13C MRS:

13C magnetic resonance spectroscopy

α-KG:

α-ketoglutarate

AAT:

Aspartate aminotransferase

Ac.CoA:

Acetyl coenzyme A

ADP:

Adenosine diphosphate

AGC:

Glutamate/aspartate exchanger (in brain AGC1 or aralar)

ANLS:

Astrocyte neuron lactate shuttle

AOAA:

Alpha-aminooxyacetic acid

ATP:

Adenosine triphosphate

AV:

Arteriovenous

BCAA:

Branched chain amino acid

BCAT:

Branched chain amino acid transaminase

BCATc:

Cytosolic branched chain amino acid transferase

BCATm:

Mitochondrial branched chain amino acid transferase

DNA, RNA:

Deoxyribonucleic acid, ribonucleic acid

GABA:

γ-aminobutyric acid

GABA-T:

GABA transaminase

GAD65, GAD67:

Glutamate amino decarboxylase 65 and 67 KD isoforms

GAT1, GAT2, GAT3:

GABA transporters 1, 2, 3

GDH:

Glutamate dehydrogenase

GLAST:

Glutamate aspartate transporter

GLT-1:

Glutamate type 1 transporter

GS:

Glutamine synthase

KIC:

Alpha-ketoisocaproic acid

MAS:

Malate-aspartate shuttle

MCT1:

Monocarboxylic acid transporter 1

MCT2, MCT3:

Monocarboxylic acid transporters 2, 3

MCTs:

Monocarboxylic acid transporters

NADH/NAD+ :

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

OAA:

Oxaloacetate

PAG:

Phosphate activated glutaminase

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase complex

SAT1, SAT2:

System A glutamine transporters 1 and 2

SN1:

System N glutamine transporter 1

SSA:

Succinic semialdehyde

TCA cycle:

Tricarboxylic acid cycle

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Acknowledgements

D.L.R. acknowledges support from the National Institute of Health grant R01NS087568A.

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  1. Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China

    Leif Hertz

  2. Magnetic Resonance Research Center, Radiology and Biomedical Engineering, Yale University, New Haven, CT, USA

    Douglas L. Rothman

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Correspondence to Douglas L. Rothman .

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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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Hertz, L., Rothman, D.L. (2016). Glucose, Lactate, β-Hydroxybutyrate, Acetate, GABA, and Succinate as Substrates for Synthesis of Glutamate and GABA in the Glutamine–Glutamate/GABA 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_2

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