9 Neurotransmitter Synthesis and Storage

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Neurotransmitters are chemical messengers that enable communication between neurons by transmitting signals across synapses. They are classified into small molecule neurotransmitters, which are synthesized in the terminal, and neuropeptides, which are synthesized in the soma. Each neurotransmitter type follows specific synthesis, storage, and transport processes, allowing diverse functions in the nervous system.

Neurotransmitters

A few criteria must be met for a molecule to be called a neurotransmitter. First, the transmitter must be synthesized within in the presynaptic neuron. Second, the transmitter must be released by the presynaptic neuron in response to stimulation. Third, when a postsynaptic neuron is treated with the transmitter by a researcher, the molecule must cause the same effect in the postsynaptic neuron as when it is released by a presynaptic neuron.

There are two main categories of neurotransmitters: small molecule transmitters and peptide transmitters. Synthesis and storage of these neurotransmitter groups differ. Small molecule neurotransmitters are synthesized and stored in the terminal for fast release. Neuropeptides are synthesized in the cell body and must be transported to the terminal, which can lead to slower release. Additionally, a neuron typically will synthesize and release only one type of small molecule neurotransmitter but can synthesize and release more than one neuropeptide.

Small Molecule Transmitters

Small molecule transmitters are synthesized in the synaptic terminal

The small molecule transmitters can be divided into two main groups: amino acid neurotransmitters and biogenic amines, also called monoamines. In addition to acting as neurotransmitters, the amino acids glutamate and glycine are used to synthesize proteins in all cell types throughout the body. GABA (Ɣ-Aminobutyric acid) is a metabolite of glutamate but is not used in protein synthesis in the body. The biogenic amines include serotonin and histamine, and the subgroup the catecholamines dopamine, norepinephrine, and epinephrine. Acetylcholine does not fit into either division but is still considered a small molecule neurotransmitter.

A diagram organizing small molecule neurotransmitters by chemical structure into categories: acetylcholine (standalone), amino acid transmitters (glutamate, GABA, glycine), and biogenic amines including serotonin and histamine, with catecholamines (dopamine, norepinephrine, epinephrine) as a subgroup, showing chemical structures for each. Link to detailed alternative text in caption.
Figure 9.1. Classification of small molecule neurotransmitters by chemical structure. Amino acid transmitters (glutamate, GABA, glycine) share amino acid structures. Biogenic amines include serotonin (indole ring) and histamine (imidazole ring). Catecholamines—a subgroup of biogenic amines sharing a catechol ring—include dopamine, norepinephrine, and epinephrine, which differ by progressive addition of hydroxyl and methyl groups. Acetylcholine, with its unique ester structure, stands alone. This classification reflects shared synthesis pathways and metabolic enzymes. ‘Small Molecule Neurotransmitters’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Synthesis and Storage of Small Molecule Transmitters

Most small molecule neurotransmitters are synthesized by enzymes that are located in the cytoplasm (the exception is norepinephrine, see below). This means that small molecule neurotransmitters can be synthesized and packaged for storage in the presynaptic terminal using enzymes present in the terminal.

Acetylcholine

Acetylcholine is best known for its role at the neuromuscular junction, the synapse between a motor neuron and the muscle fiber. In the presynaptic terminal, acetylcholine is synthesized from acetyl coenzyme A (acetyl CoA) and choline via the enzyme choline acetyltransferase. The level of enzyme activity is the rate-limiting step in the synthesis pathway. Acetylcholine is packaged into vesicles for storage in the terminal via the vesicular acetylcholine transporter (VAChT).

A diagram showing acetylcholine synthesis in a presynaptic terminal, where choline acetyltransferase converts acetyl CoA and choline into acetylcholine, which is then packaged into synaptic vesicles by the vesicular acetylcholine transporter. Link to detailed alternative text in caption.
Figure 9.2. Acetylcholine synthesis and storage. Choline acetyltransferase (ChAT) converts acetyl CoA and choline into acetylcholine, the rate-limiting step in the pathway. Acetylcholine is packaged into vesicles by the vesicular acetylcholine transporter (VAChT). ‘Acetylcholine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Glutamate

Glutamate is an amino acid transmitter and is the primary excitatory neurotransmitter in the brain. In the presynaptic terminal, glutamine is converted into glutamate via the enzyme glutaminase, which is the rate-limiting step in the synthesis pathway. Glutamate is packaged into vesicles for storage via the vesicular glutamate transporter.

A diagram showing glutamate synthesis in a presynaptic terminal, where glutaminase converts glutamine into glutamate, which is then packaged into synaptic vesicles by the vesicular glutamate transporter. Link to detailed alternative text in caption.
Figure 9.3. Glutamate synthesis and storage. Glutaminase converts glutamine into glutamate, the rate-limiting step in the pathway. Glutamate is packaged into vesicles by the vesicular glutamate transporter (VGLUT). ‘Glutamate Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

GABA

Glutamate is then used to synthesize GABA, another amino acid transmitter and the primary inhibitory neurotransmitter in the brain. In the presynaptic terminal, glutamate is converted into GABA via the enzyme glutamic acid decarboxylase, which like the other synthesis pathways is the rate-limiting step. GABA is packaged into vesicles for storage in the terminal via the vesicular inhibitory amino acid transporter.

A diagram showing GABA synthesis in a presynaptic terminal, where glutamic acid decarboxylase converts glutamate into GABA, which is then packaged into synaptic vesicles by the vesicular inhibitory amino acid transporter. Link to detailed alternative text in caption.
Figure 9.4. GABA synthesis and storage. Glutamic acid decarboxylase (GAD) converts glutamate into GABA, the rate-limiting step in the pathway. GABA is packaged into vesicles by the vesicular inhibitory amino acid transporter (VIAAT). ‘GABA Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Glycine

Glycine is another inhibitory amino acid neurotransmitter, but unlike GABA, it is more common in the spinal cord than in the brain. Serine hydroxymethyltransferase converts the amino acid serine into glycine in the presynaptic terminal. The rate limiting step for glycine synthesis occurs earlier in the pathway prior to serine synthesis. Glycine is packaged into vesicles by the vesicular inhibitory amino acid transporter like GABA.

A diagram showing glycine synthesis in a presynaptic terminal, where serine hydroxymethyltransferase converts serine into glycine, which is then packaged into synaptic vesicles by the vesicular inhibitory amino acid transporter. Link to detailed alternative text in caption.
Figure 9.5. Glycine synthesis and storage. Serine hydroxymethyltransferase converts serine into glycine. Glycine is packaged into vesicles by the vesicular inhibitory amino acid transporter (VIAAT), the same transporter used by GABA. ‘Glycine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Dopamine

Dopamine, a catecholamine transmitter, plays many roles in the nervous system, but it is best known for its roles in reward and movement. In the presynaptic terminal, the amino acid tyrosine is converted into DOPA via tyrosine hydroxylase, which is the rate limiting step in the synthesis of all the catecholamines. DOPA is then converted to dopamine by DOPA decarboxylase. Dopamine is packaged into synaptic vesicles by the vesicular monoamine transporter.

A diagram showing dopamine synthesis in a presynaptic terminal through a two-step process: tyrosine hydroxylase converts tyrosine to DOPA, then DOPA decarboxylase converts DOPA to dopamine, which is packaged into vesicles by the vesicular monoamine transporter. Link to detailed alternative text in caption.
Figure 9.6. Dopamine synthesis and storage. Tyrosine hydroxylase converts tyrosine into DOPA, the rate-limiting step for all catecholamine synthesis. DOPA decarboxylase then converts DOPA into dopamine. Dopamine is packaged into vesicles by the vesicular monoamine transporter (VMAT). ‘Dopamine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Norepinephrine

In neurons that release norepinephrine, which is another catecholamine transmitter, once dopamine is packaged into the synaptic vesicles, a membrane-bound enzyme called dopamine beta-hydroxylase converts dopamine into norepinephrine. Therefore, unlike the other small molecule neurotransmitters, norepinephrine is synthesized within the vesicles, not in the cytoplasm. Like dopamine, the rate limiting step of this synthesis pathway is the activity of tyrosine hydroxylase.

A diagram showing norepinephrine synthesis within synaptic vesicles, where the membrane-bound enzyme dopamine beta-hydroxylase converts packaged dopamine into norepinephrine, making it unique among small molecule neurotransmitters. Link to detailed alternative text in caption.
Figure 9.7. Norepinephrine synthesis and storage. Dopamine beta-hydroxylase, a membrane-bound enzyme in the vesicle, converts dopamine into norepinephrine after packaging. Unlike other small molecule neurotransmitters, norepinephrine is synthesized within vesicles rather than in the cytoplasm. ‘Norepinephrine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Epinephrine

Epinephrine, also called adrenaline, is a catecholamine, but it is often considered a hormone instead of a neurotransmitter. Epinephrine is primarily released by the adrenal medulla into the circulation; it is used as a neurotransmitter in only a small number of neurons. Epinephrine is synthesized from norepinephrine in the cytoplasm by the enzyme phenylethanolamine-N-methyltransferase, so epinephrine synthesis requires norepinephrine to exit the vesicles where it was synthesized. After synthesis in the cytoplasm, epinephrine is repackaged into vesicles via the vesicular monoamine transporter.

A diagram showing epinephrine synthesis where norepinephrine exits vesicles and is converted to epinephrine by phenylethanolamine-N-methyltransferase in the cytoplasm, then repackaged into vesicles by the vesicular monoamine transporter. Link to detailed alternative text in caption.
Figure 9.8. Epinephrine synthesis and storage. Norepinephrine exits vesicles and is converted to epinephrine by phenylethanolamine-N-methyltransferase in the cytoplasm. Epinephrine is then repackaged into vesicles by the vesicular monoamine transporter (VMAT). ‘Epinephrine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Serotonin

Serotonin, a biogenic amine neurotransmitter, is known for its role in mood. Tryptophan is converted into 5-hydroxytryptophan by tryptophan hydroxylase. This is also the rate-limiting step of the synthesis pathway. Then aromatic L-amino acid decarboxylase converts the 5-hydroxytryptophan into serotonin. Serotonin is packaged into vesicles by the vesicular monoamine transporter similar to other monoamine neurotransmitters like dopamine and norepinephrine.

A diagram showing serotonin synthesis in a presynaptic terminal through a two-step process: tryptophan hydroxylase converts tryptophan to 5-hydroxytryptophan, then aromatic L-amino acid decarboxylase converts it to serotonin, which is packaged by the vesicular monoamine transporter. Link to detailed alternative text in caption.
Figure 9.9. Serotonin synthesis and storage. Tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan, the rate-limiting step in the pathway. Aromatic L-amino acid decarboxylase then converts 5-hydroxytryptophan into serotonin. Serotonin is packaged into vesicles by the vesicular monoamine transporter (VMAT). ‘Serotonin Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Histamine

Finally, histamine is another biogenic amine transmitter that is synthesized from histidine through the action of histidine decarboxylase, the rate limiting step of the pathway. Like the other monoamine neurotransmitters, it is packaged into synaptic vesicles via the vesicular monoamine transporter.

A diagram showing histamine synthesis in a presynaptic terminal, where histidine decarboxylase converts histidine into histamine in a single step, which is then packaged into synaptic vesicles by the vesicular monoamine transporter. Link to detailed alternative text in caption.
Figure 9.10. Histamine synthesis and storage. Histidine decarboxylase converts histidine into histamine, the rate-limiting step in the pathway. Histamine is packaged into vesicles by the vesicular monoamine transporter (VMAT). ‘Histamine Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Synthesis and Storage of Neuropeptides

Neuropeptides are synthesized in the cell body and transported to the synaptic terminal

Neuropeptides are a short string of amino acids and are known to have a wide range of effects from emotions to pain perception. Unlike small molecule neurotransmitters, neuropeptides are synthesized in the cell body and transported to the axon terminal. Like other proteins, neuropeptides are synthesized from mRNA into peptide chains made from amino acids. In most cases, a larger precursor molecule called the prepropeptide is translated into the original amino acid sequence in the rough endoplasmic reticulum. The prepropeptide is processed further to the propeptide stage. The remaining processing and packaging of the final neuropeptide into a vesicle occurs in the Golgi apparatus. The peptides are packaged into vesicles that are significantly larger than the vesicles that store the small molecule transmitters. These large vesicles must then move from the soma to the terminal.

A diagram showing neuropeptide synthesis in the cell body, from gene transcription through translation of prepropeptides in the rough endoplasmic reticulum, processing in the Golgi apparatus, and packaging into vesicles for transport to axon terminals. Link to detailed alternative text in caption.
Figure 9.11. Neuropeptide synthesis and processing. Neuropeptide genes in the nucleus are transcribed and translated into prepropeptides in the rough endoplasmic reticulum. The signal sequence is cleaved to form propeptides, which are processed in the Golgi apparatus into mature peptides. The peptides are packaged into vesicles and transported to the axon terminal. ‘Neuropeptide Synthesis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Axonal Transport

The packaged peptides need to be transported to the presynaptic terminals to be released into the synaptic cleft. Organelles, vesicles, and proteins can be moved from the cell body to the terminal via anterograde transport or from the terminal to the cell body via retrograde transport. Anterograde transport can be either fast or slow.

The packaged neuropeptides are transported to the synaptic terminals via fast anterograde axonal transport mechanisms.

A diagram showing bidirectional axonal transport in a neuron, with anterograde transport moving components from the cell body toward the terminal and retrograde transport moving components from the terminal back to the cell body. Link to detailed alternative text in caption.
Figure 9.12. Axonal transport mechanisms. Anterograde transport moves components from the cell body toward the terminal, including neuropeptide-containing vesicles. Retrograde transport moves components from the terminal toward the cell body for degradation or recycling. ‘Axonal Transport’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Conclusion

The diversity of neurotransmitters and their synthesis pathways underpins the complexity of neuronal communication. Small molecule neurotransmitters ensure rapid signaling, while neuropeptides provide more prolonged and modulatory effects. Together, they enable precise regulation of neural circuits essential for behavior and physiology.

Key Takeaways

  • A molecule is classified as a neurotransmitter if it is synthesized in the presynaptic neuron, released in response to stimulation, and elicits the same effect in the postsynaptic neuron as experimentally applied.
  • Small molecule neurotransmitters (e.g., glutamate, GABA, acetylcholine) are synthesized and stored in the terminal, while neuropeptides are synthesized in the soma and transported to terminals.
  • Amino acids, biogenic amines (e.g., dopamine, serotonin), and acetylcholine are small molecule neurotransmitter groups, each with unique synthesis pathways.
  • Neuropeptides are synthesized from precursor molecules in the rough ER, processed in the Golgi apparatus, and transported via fast anterograde transport.
  • Anterograde transport moves components toward the axon terminal, while retrograde transport moves them back to the cell body.

Important Terminology

Test Yourself!

Try the quiz more than once to get different questions!

  • For each neurotransmitter below, which enzyme is responsible for the rate-limiting step in the synthesis pathway, which enzyme is responsible for the final step of the synthesis pathway, and which enzyme is responsible for packaging of the transmitter into vesicles
    • Acetylcholine
    • Glutamate
    • GABA
    • Glycine
    • Dopamine
    • Norepinephrine
    • Epinephrine
    • Serotonin
    • Histamine

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Foundations of Neuroscience Copyright © 2021 by Casey Henley is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted.

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