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Biosynthesis of Amino Acid Neurotransmitters

Amino acid neurotransmitters are all products of intermediary metabolism with the exception of GABA. Unlike all the other amino acid neurotransmitters, GABA is not used in protein synthesis and is produced by an enzyme (glutamic acid decarboxylase; GAD) uniquely located in neurons. Antibodies to GAD can be used to identify neurons that release GABA.

Glutamate and Aspartate

Glutamate and aspartate are products of the Kreb's cycle, and both have excitatory effects in the CNS. They are produced in the mitochondria, transported into the cytoplasm, and packaged into synaptic vesicles (Figure 13.4). Specific high-affinity enzymes are responsible for packaging glutamate into vesicles.

The actions of glutamate are terminated by high-affinity uptake systems in neurons and glia (represented by red cylinders in the neuron and glia membranes). Under normal circumstances most uptake is back into the neuron and this glutamate can immediately be pumped into vesicles for subsequent release. When neuronal activity is high, extracellular glutamate concentration exceeds the capacity of neuronal uptake. At this point, uptake systems in glial cells help absorb the excess glutamate. However, glutamate is not permeable to the plasma membrane. To recycle the glutamate taken up into glial cells, an enzymatic reaction catalyzed by glutamine synthase produces glutamine from glutamate (Figure 13.4). Glutamine is freely permeable to the glial and neuronal plasma membranes and diffuses back into the neuron. The neuronal enzyme glutaminase then metabolizes glutamine into glutamate where it can then be packaged into synaptic vesicles for another round of release (Figure 13.4).

Glycine

Figure 13.5

Glycine is the main neurotransmitter that mediates the inhibitory actions of spinal cord interneurons. It is also present in lower amounts throughout the nervous system. Glycine is synthesized from serine in the mitochondria (Figure 13.5). The reaction is catalyzed by the enzyme serine transhydroxymethylase (Figure 13.5; click on box). Like glutamate, high-affinity uptake systems remove glycine from the synaptic cleft, which can then be repackaged into vesicles.

The binding of glycine to its receptor on postsynaptic neurons is blocked by the poison strychnine, thus blocking glycine's inhibitory actions (Figure 13.5). The block of inhibition leads to hyperexcitation and typically a patient with strychnine poisoning asphyxiates due to an inability to relax the diaphragm. More details on the nature of glycine receptors are provided later in this chapter. (You can move forward to it now, but be aware that you are advancing FORWARD.)

GABA

Figure 13.6

GABA mediates the majority of inhibitory synaptic actions in the CNS. GABA is synthesized from glutamate in a reaction catalyzed by glutamic acid decarboxylase (GAD; Figure 13.6). Antibodies to GAD can be used to identify GABAergic neurons. Like the other amino acid transmitters, GABA's actions are terminated by high affinity uptake systems in neurons and glia. Neuronal uptake permits immediate repackaging into vesicles for release. Compared with glutamate, a more elaborate set of reactions is necessary to return GABA to the neuron when it is taken up by glial cells. Some of these enzymes are shared with those for returning released glutamate to neurons described in Figure 13.4. GABA is first converted back into glutamate by the mitochondrial enzyme GABA transaminase (GABA-T; Figure 13.6; click on box) using the -COOH group from alpha-ketoglutarate. This pathway is sometimes referred to as the "GABA shunt". The glutamate is then converted to glutamine by the enzyme glutamine synthase and glutamine diffuses back into the neuron. Finally, glutaminase converts glutamine into glutamate, which can again serve as a substrate for GAD, completing the cycle.

Ca²⁺-Dependent Release

All of these amino acid neurotransmitters are released by Ca²⁺-dependent exocytosis at presynaptic specializations as discussed in Chapter 8, Part 7 and Chapter 10, Part 4. All vesicles (both small molecule and neuropeptide) also contain ATP that is co-released when these vesicles fuse with the membrane. ATP and its degradation product adenosine are themselves neurotransmitter molecules (termed purinergic transmission) that can also modify the pre- or postsynaptic cell's response if the appropriate receptors are present. For example, adenosine is a potent inhibitor of neurotransmitter release from presynaptic terminals.

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