Regulation of extracellular glutamate concentration

Glutamic acid, commonly known as glutamate, is an amino acid that is ubiquitously present in cells, tissues and organs. In the CNS, glutamate also serves as the main excitatory neurotransmitter, which is exocytotically released from presynaptic terminals. This imposes severe restrictions on the brain glutamate homeostatic system, which must (1) prevent contamination by nonsynaptically released glutamate, (2) allow rapid removal of glutamate from the synaptic cleft, and (3) provide the means for rapid replenishment of the glutamate-releasable pool. As if these are not enough, background extracellular glutamate concentration should always be kept very low, as glutamate in excess is highly neurotoxic. Precise regulation of extracellular concentration of glutamate is, therefore, of paramount importance for brain function.

The first cornerstone of this regulation is laid by blood-brain barrier, which does not allow glutamate from the circulation to enter the CNS; as a consequence, all glutamate in the brain must be synthesized within the brain. A second important part of the glutamate homeostatic system is created by the specific morphological organization of glutamatergic synapses, which are often completely enclosed by the membrane of astrocytic perisynaptic processes; such an organization prevents glutamate from spilling over from the synaptic cleft and contaminating nearby synapses. Third, the glutamate in the synaptic cleft is very rapidly removed by glutamate transporters (see also Chapter 5.7), which are located either in astroglial membranes or in the postsynaptic neuronal membrane. The presynaptic terminal is devoid of glutamate transporters.

Astroglial cells represent the main sink of glutamate in the brain (Figure 7.10); from the bulk of glutamate released during synaptic transmission, about 20 per cent is accumulated into postsynaptic neurones and the remaining 80 per cent is taken up by perisynaptic astrocytes. Thus, synaptic transmission is associated with a continuous one-directional flow of glutamate into astroglial cells. Quite obviously, such a process would rapidly deplete the pool of releasable neuro-transmitter. Astrocytes therefore have a special system for recovering glutamate to the presynaptic terminal. After being accumulated by astrocyte, glutamate is converted into glutamine, and it is this glutamine that is released by the astrocyte into the extracellular space for subsequent uptake into presynaptic neurones - the so-called glutamate-glutamine shuttle (Figure 7.10); as glutamine is physiologically inactive, its appearance in the extracellular milieu is harmless. Conversion of glutamate to glutamine is catalyzed by glutamine synthetase (highly expressed by astrocytes, and used as a specific marker) and requires energy (one ATP molecule

Glutamate Recycling Astrocyte

Figure 7.10 Glutamate uptake by glial and neuronal cells - the glutamate-glutamine shuttle. Glutamate released during synaptic activity is removed from the cleft by glutamate transporters; about 80 per cent of glutamate is accumulated by astrocytes and ~20 per cent by postsynaptic neurones; presynaptic terminals do not accumulate glutamate. After entering the astrocyte, glutamate is converted into glutamine, which is then transported back to the presynaptic terminal, where it is converted into glutamate and accumulated into synaptic vesicles. This recycling of glutamate by astrocytes is known as the glutamate-glutamine shuttle

Figure 7.10 Glutamate uptake by glial and neuronal cells - the glutamate-glutamine shuttle. Glutamate released during synaptic activity is removed from the cleft by glutamate transporters; about 80 per cent of glutamate is accumulated by astrocytes and ~20 per cent by postsynaptic neurones; presynaptic terminals do not accumulate glutamate. After entering the astrocyte, glutamate is converted into glutamine, which is then transported back to the presynaptic terminal, where it is converted into glutamate and accumulated into synaptic vesicles. This recycling of glutamate by astrocytes is known as the glutamate-glutamine shuttle per conversion); importantly glutamate uptake into astrocytes triggers glucose hydrolysis, which provides ATP, and links neuronal activity with the supply of energy substrates (see Chapter 7.10 for details). When glutamine enters the presynaptic neurone it is hydrolysed to glutamate; this process, which is assisted by phosphate-activated glutaminase, does not require energy. The newly synthesized glutamate is concentrated in synaptic vesicles, endowed with specific vesicular glutamate transporters. This is the endpoint for the glutamate-glutamine shuttle, which allows for sustained glutamatergic synaptic transmission.

Similarly important is the involvement of astroglial glutamate uptake in preventing excitotoxic accumulation of high glutamate levels in the extracellular space, and removal of astrocytes from neuronal glial co-cultures, for example, greatly increases neuronal vulnerability and amplifies neuronal death.

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