Neurochemistry

Due to the major role of glutamate, not only as a component of proteins but also as a key step in intermediate metabolism, the production and metabolism of the amino acid are compartmentalised in neurons. It may be that the transmitter pool of glutamate uses the amino acid from any source given that it can be produced from such diverse origins as glucose, aspartate, glutamine and oxoglutarate. Once release occurs there are high-affinity uptake sites in both terminals and glia that remove the transmitter from the synaptic cleft (Fig. 10.2).

These points have important functional implications. While neuronal glutamate may come from glucose via pyruvate, the Krebs cycle and transamination of alpha-oxoglutamate, it seems likely that most of the transmitter originates from the deamination of glutamine. After release, the high-affinity uptake sites (transporters)

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd

Figure 10.1

glutamate

Structures of the transmitters and synthetic agonists at the various receptors for

Figure 10.1

glutamate

Structures of the transmitters and synthetic agonists at the various receptors for remove glutamate from the synapse, partly back into the nerve terminal or more probably into adjacent glial cells. In the latter, it is converted by glutamine synthetase into glutamine which then passes back into the extracellular fluid (the CSF levels are high, of the order of 0.5mM) to be taken up by the glutamate nerve terminal. Here it is deaminated to neurotransmitter available glutamate by mitochondrial glutaminase. Thus there is a conservation rather than a net synthesis of glutamate. This complex but very general biochemical process provides very little opportunity for drug modification of glutamate synthesis or metabolism.

Unlike other transmitter systems, there are no obvious mechanisms for dampening glutamate release. Presynaptic autoreceptors for glutamate are mostly of the kainate type (see below) and appear to act as positive rather than negative influences on further release of the amino acid. Although poorly characterised at present, inhibitory autoreceptors of the metabotropic type of receptors may act to inhibit release of glutamate.

Was this article helpful?

0 0

Post a comment