Brain Glutamate Handling An Overview

Glutamic acid is the major excitatory neurotransmitter of the mammalian nervous system. This amino acid must be quickly cleared from the extracellular fluid following its release from nerve endings. A persistently high glutamate concentration in the synaptic cleft would obscure the high signal-to-noise ratio that is essential to effective neurotransmission. By efficiently removing glutamate from the extracellular space, the system is repoised to detect the release of additional glutamate from presynaptic neurons. In addition, an untoward external glutamate level would favor the development of excitotoxicity because of excessive stimulation of vulnerable neurons. Considerable evidence now points to astrocytes as the major site of brain glutamate uptake (Fig. 2) (10-12). Glial cells are favored with a plenitude of excitatory amino acid transporters that abet the rapid and efficient removal of glutamate from the synapse. They also have

Fig. 2. The glutamine-glutamate cycle of brain. Glutamate released from neurons is preferentially taken up into astrocytes, which then convert glutamate to glutamine. It is as glutamine, a nonneuroactive amino acid, that glutamate is restored to the neurons. Astrocytes release glutamine, which is accumulated by neurons and enzymatically converted back to glutamate via phosphate-dependent glutaminase.

Fig. 2. The glutamine-glutamate cycle of brain. Glutamate released from neurons is preferentially taken up into astrocytes, which then convert glutamate to glutamine. It is as glutamine, a nonneuroactive amino acid, that glutamate is restored to the neurons. Astrocytes release glutamine, which is accumulated by neurons and enzymatically converted back to glutamate via phosphate-dependent glutaminase.

a relatively high membrane potential, an important consideration in enabling the action of sodium-dependent transport systems for excitatory amino acids (13).

Following the uptake of glutamate by the glia, the system must somehow restore this amino acid to the neuronal pools from which it originated. Releasing glutamate directly into the extracellular fluid would not be a workable solution because the extracellular "trafficking" of this excitatory neurotransmitter would expose the system to the risk of depolarization. Instead, astrocytes convert glutamate to glutamine via the glutamine synthetase reaction, a pathway that in brain is dependent on adenosine triphosphate (ATP) and is almost exclusively localized to the astrocytes (14,15). The ammonia that is a coreactant for the glutamine synthetase reaction is derived either from internal sources or from the blood (16). Glia then release glutamine to neurons, where this non-neuroactive amino acid is enzymatically cleaved back to glutamate via phosphate-dependent glutaminase, a mitochondrial enzyme (17).

The series of reactions that begins with the release of glutamate from nerve endings and finishes with the cleavage of glutamine to glutamate is called the "glutamate-gluta-mine cycle". First propounded more than 20 yr ago, the cycle remains the centerpiece of our thinking regarding brain amino acid metabolism (18). This model provides an excellent framework with which to develop concepts of brain nitrogen metabolism, but, like all models, it necessarily oversimplifies important details.

One aspect of the system that the glutamate-glutamine cycle ignores is the question of the external sources of -NH2 groups that the brain, like any other organ, must import to replace inevitable losses from the system. Virtually no glutamate or glutamine is directly taken up from blood to brain (19,20), and alternate sources of nitrogen must become available. One likely nitrogen donor is leucine, which is actively transported into the central nervous system and is which readily transaminated by brain to glutamate and ketoleucine (20-24). Indeed, studies performed with [15N]leucine have suggested that at least one-third of all brain nitrogen may have derived from leucine alone, with significant contributions also coming form valine and isoleucine, the other branched-chain amino acids (25). There may be an intricate cycling of leucine between astrocytes and neurons such that 2-oxoisocaproate, the ketoacid of leucine, is released to neurons, where it can be converted back to leucine, in the process "buffering" glutamate (24).

The model implicit in the glutamate-glutamine cycle ignores a second pivotal aspect of brain nitrogen handling, namely, that amino acids such as glutamate, glutamine, and aspartate not only are critical to neurotransmission but also function as essential metabolic intermediates. As noted earlier, an appreciable fraction of glucose carbon flows through relatively large pools of these amino acids before final combustion to CO2. If the brain respires on a fuel other than glucose—and the ketone bodies are the most important alternate source—then we might anticipate that this fundamental shift in the metabolic "set" of the system would significantly affect brain glutamate handling. This appears to be the case.

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