Acetylcholine synthesis Figure 7-1. A: Acetylcholine is synthesized from choline and acetyl coenzyme A by choline acetyltransferase (ChAT). Acetylcholinesterase (AChE) and several other esterases break acetylcholine down into choline and acetate. B: The synthesis, packaging, release, breakdown, and uptake mechanisms involved in cholinergic transmission are illustrated in situ. Choline (light blue symbol as in A) from dietary sources and from the extracellular breakdown of released acetylcholine (dark blue symbol as in A) is taken up into cells by the choline transporter. Within cholinergic terminals, choline acetyltransferase catalyzes the synthesis of acetylcholine from choline and acetyl coenzyme A. The vesicular acetylcholine transporter shuttles ACh from the cytoplasm into synaptic vesicles. Upon release, acetylcholine is rapidly degraded by acetylcholinesterase. Within the terminal, esterases, including but not limited to acetylcholinesterase, break down acetylcholine.

Catecholamine synthesis Figure 7-2 A: Tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis, converts tyrosine into DOPA. Aromatic amino acid decarboxylase converts DOPA into dopamine, and dopamine β-hydroxylase converts dopamine into norepinephrine. Finally, phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine into epinephrine. All of these reactions except the conversion of dopamine into norepinephrine take place in the cytoplasm, and this exceptional reaction takes place within the synaptic vesicle. B: In dopaminergic, or dopamine-containing, terminals, the vesicular monoamine transporter transports dopamine, made in the cytoplasm, into synaptic vesicles. Neither dopamine β-hydroxylase nor PNMT are found in dopaminergic terminals. C: In noradrenergic, or norepinephrine-containing, terminals, the vesicular monoamine transporter transports dopamine, made in the cytoplasm, into synaptic vesicles and dopamine β-hydroxylase (DβH), present in the vesicle, then converts dopamine into norepinephrine within the synaptic vesicle. PNMT is not present in noradrenergic terminals D: The adrenergic terminal builds upon the noradrenergic terminal by reverse transporting norepinephrine out of the synaptic vesicle and into the cytoplasm. PNMT then converts norepinephrine into epinephrine within the cytoplasm. Cytosolic epinephrine is transported into the synaptic vesicle by the vesicular monoamine transporter. Note that adrenergic, or epinephrine-containing, terminals contain all of the catecholaminergic enzymes. B-D: The dominant neurotransmitter in the synaptic vesicle is shown in italics. In dopaminergic terminals (B), only dopamine is synthesized and transported into vesicles. However, in noradrenergic terminals (C), norepinephrine predominates but lesser amounts of dopamine are present. Similarly, in adrenergic vesicles (D), some dopamine and norepinephrine are present along with mostly epinephrine.

Serotonin synthesis Figure 7-3. Tryptophan hydroxylase catalyzes the formation of tryptamine from tryptophan and is the rate-limiting step in the synthesis of serotonin. Aromatic amino acid decarboxylase, the same enzyme that converts DOPA into dopamine, decarboxylates tryptamine to form serotonin. Serotonin is transported into vesicles by the vesicular monoamine transporter, the same transporter that carries catecholamines into vesicles.

Monoamine uptake transporters Figure 7-4. A: Synaptic terminals that release norepinephrine (blue NE, left), dopamine (red DA, middle), or serotonin (green 5HT, right) have a transporter with high affinity for the transmitter released. Yet, each of these transporters has some affinity for the other monoamines. The norepinephrine transporter (NET) has nearly equivalent affinity for dopamine as for norepinephrine. The dopamine transporter (DAT) has low affinity for serotonin in addition to high affinity for dopamine. Finally, the serotonin transporter (SERT) has low affinity for both dopamine and norepinephrine, as well as high affinity for serotonin. The high-affinity monoamine transporters are located perisynaptically, meaning near the synapse but not at the synaptic release site. Note that the synaptic terminals illustrated are cartoons of boutons. In reality, many monoaminergic release sites are varicosities. B: Two low-affinity transporters, the organic cation transporter and the plasma membrane monoamine transporter, are present on neighboring cells and contribute to the removal of monoamines from the extracellular space. Because of the high concentration of monoamines released, low-affinity uptake is effective even when located at some distance from the release site.

Glutamate synthesis Figure 7-5. Astrocytes and neurons both participate in the synthesis, uptake, and degradation of glutamate (yellow symbol). Within synaptic terminals, glutamate is synthesized from glutamine by the mitochondrial enzyme, glutaminase. Glutamate is also one of the by-products of the Krebs cycle in all cells. Glutamate within synaptic terminals is transported into synaptic vesicles by the vesicular glutamate transporter (VGLUT), and after release, is taken up by both astrocytes and terminals through the excitatory amino acid transporter (EAAT). Within astrocytes, glutamate is converted into glutamine by glutamine synthetase. The molecules involved in transporting glutamine out of astrocytes and into terminals are not yet identified molecularly. Yet, glutamine does make it out of astrocytes and into neuronal terminals.

GABA synthesis Figure 7-6. Astrocytes and neurons both participate in the synthesis, uptake, and degradation of γ-aminobutyric acid (GABA). GABA (blue oval) is formed from glutamate by glutamic acid decarboxylase (GAD) and then put into vesicles by the vesicular inhibitory amino acid transporter (VIAAT). After release, GABA is taken up by astrocytes and terminals by the GABA transporter (GABA-T). In synaptic terminals, GABA is recycled to fill synaptic vesicles anew, whereas in astrocytes, GABA is converted to succinate by GABA transaminase. Succinate is used in the Krebs cycle.