2 Neuroscience2.5 Neurochemistry and neurophysiology
2.5.2 Transmitter synthesis, storage, release and uptake; ion channels and calcium flux
2 min read2 figures
Written by Resident Doctor Committee · Published
Where transmitters are made
Small-molecule transmitters are made in the nerve terminal by enzymes that the cell body supplies.
Neuropeptide precursors are made on the rough endoplasmic reticulum, and the Golgi apparatus modifies, sorts and packages them into vesicles for storage and transport.
Synthesis pathways
Transmitter | Made from | Enzyme for last step | Note |
|---|---|---|---|
Serotonin | 5-hydroxytryptophan, from tryptophan | Aromatic L-amino acid decarboxylase | Tryptophan hydroxylase is rate-limiting |
Dopamine | L-DOPA, from tyrosine | Aromatic L-amino acid decarboxylase | Tyrosine hydroxylase is rate-limiting |
Noradrenaline | Dopamine | Dopamine beta-hydroxylase | Happens inside vesicles |
Adrenaline | Noradrenaline | Phenylethanolamine N-methyltransferase | Cortisol induces the enzyme |
Acetylcholine | Choline and acetyl coenzyme A | Choline acetyltransferase | Mitochondria make acetyl coenzyme A from glucose |
GABA | Glutamate | Glutamic acid decarboxylase | Cofactor is pyridoxal phosphate |
Glutamate | Glutamine | Glutaminase | Astrocytes supply glutamine |
Histamine | Histidine | Histidine decarboxylase | One step, in the tuberomammillary nucleus |
Serotonin comes from the essential amino acid tryptophan in two steps.
Dopamine comes from phenylalanine, then tyrosine, then L-DOPA, its direct precursor.
Tyrosine hydroxylase converts tyrosine to L-DOPA, and this is the rate-limiting step for all the catecholamines.
Aromatic L-amino acid decarboxylase (DOPA decarboxylase) decarboxylates hydroxylated aromatic amino acids, so one enzyme makes both dopamine and serotonin.
Phenylethanolamine N-methyltransferase transfers a methyl group from S-adenosylmethionine to noradrenaline in the adrenal medulla.
Choline acetyltransferase activity falls in the cortex in Alzheimer's disease, reflecting loss of projections from the nucleus basalis.
Serotonin outside the brain, and melatonin
Most serotonin in the body is made by enterochromaffin cells in the gut, and it does not cross the blood-brain barrier to supply the brain.
Melatonin is made in the pineal gland from serotonin: acetylation gives N-acetylserotonin, then methylation gives melatonin.
Storage and calcium-triggered release
Vesicular transporters load transmitter into vesicles, using a gradient that a proton pump creates; reserpine and tetrabenazine block monoamine loading and deplete stores.
Calcium entry through presynaptic N-type or P/Q-type channels, opened by an action potential, lets synaptotagmin trigger vesicle fusion through the SNARE proteins synaptobrevin, syntaxin and SNAP-25.
Botulinum toxin disrupts this machinery at cholinergic terminals and causes flaccid paralysis.
Postsynaptic ion channels
Channel lets through | Receptors | Usual effect |
|---|---|---|
Sodium and potassium | Nicotinic, AMPA, 5-HT3 | Depolarising |
Cations, including much calcium | NMDA | Depolarising, with calcium-dependent signalling |
Chloride | GABA-A, glycine | Inhibitory in mature neurones |
Termination and breakdown
Membrane transporters take serotonin, noradrenaline and dopamine back up, and acetylcholinesterase breaks down acetylcholine.
Monoamine oxidase A is the form that preferentially breaks down serotonin, by oxidative deamination on the way to 5-hydroxyindoleacetic acid (5-HIAA).
Catechol-O-methyltransferase acts only on catechols, which carry two adjacent hydroxyl groups on a benzene ring. Serotonin is an indoleamine with a single 5-hydroxyl, so this enzyme neither makes nor breaks it down.
Astrocytes take up glutamate, convert it to glutamine with glutamine synthetase, and return glutamine, not glutamate, to the presynaptic terminal.