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

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.

Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

“…Moreover, there is no consensus regarding the enzyme catalyzing glutamate conversion to α-ketoglutarate, an essential first step in its degradation. Most authors assume that this process is catalyzed by glutamate dehydrogenase (GDH), but we have previously suggested that glutamate synthesis and degradation are coupled and both catalyzed by aspartate aminotransferase (AAT) [6,15,16]. This paper provides additional support for this concept by clarifying how AAT is capable of catalyzing the process in both directions.…”

“…Together these two fluxes, calculated from rates of oxygen consumption, are only slightly higher than the total glutamine-glutamate cycle flux determined by 13 C NMR spectroscopy (Figure 1) in the lightly anesthetized rat [10]. The return of released transmitter GABA to glutamine is complex [4,6] and will not be discussed in the present paper. The fluxes in the two directions are approximately equal (Figure 1) and a truncated TCA cycle with build-up and release of aspartate is in vivo only seen during hypoglycemia, when conversion of glutamate-derived α-KG to oxaloacetate and aspartate provides some metabolic energy [42].…”

“…EAAT4 and EAAT5 transport glutamate slowly [3] and EAAT5 is present in the retina, but it has not been demonstrated in brain [3]. Part of the released GABA is also converted to glutamate [4] and accumulated by astrocytes [5,6]. …”

“…In the brain, this reaction will not be able to remove glutamate as an excitatory amino acid, unless the generated aspartate is also disposed of. In this paper we will discuss and elucidate a previously proposed mechanism that does exactly that, because it couples astrocytic oxidation of glutamate and aspartate formation with a second phase in which de novo glutamate synthesis utilizes the nitrogen transferred to aspartate initially [6,15,16]. Glial nitrogen balance is maintained by removal of glutamate through conversion to glutamine.…”

“…Subsequently, glutamine is transferred to neurons in the glutamine-glutamate cycle together with astrocytically-accumulated, previously-released transmitter glutamate (see below). Most glutamine is accumulated by glutamatergic neurons, but some (about 20% depending on the brain region [2,4,33]) is taken up by GABAergic neurons where it is converted by glutamate decarboxylase (GAD) to GABA as previously reviewed [5,6,16,34]. …”