Neurotransmitter synthesis · Lobeworks/17

Neurotransmitter synthesis is the set of enzymatic steps by which a neuron makes its transmitters from common molecules (amino acids, choline, sugars), and it is short: most transmitters are one or two enzymes away from something every cell already has, so what makes a neuron glutamatergic, GABAergic or dopaminergic is

Neurotransmitter synthesis. Neurotransmitter synthesis is the set of enzymatic steps by which a neuron makes its transmitters from common molecules (amino acids, choline, sugars), and it is short: most transmitters are one or two enzymes away from something every cell already has, so what makes a neuron glutamatergic, GABAergic or dopaminergic is which enzymes it expresses.

The main routes fit in a few lines. Glutamate is made from glutamine by glutaminase; after release, astrocytes take it up, turn it back into glutamine and hand it to the neuron again (the glutamate-glutamine cycle). GABA is made from glutamate in one step by glutamic acid decarboxylase (GAD), so the brain's main brake is built from its main accelerator. Dopamine comes from the amino acid tyrosine in two steps, first to L-DOPA by tyrosine hydroxylase, the slowest step and the one that sets the pace, then to dopamine by a decarboxylase; serotonin comes from tryptophan by the same pattern; acetylcholine from choline and acetyl-CoA by choline acetyltransferase. Vesicular transporters then pump each transmitter into vesicles (VGLUT for glutamate, VGAT for GABA, VMAT2 for the monoamines), ready for exocytosis.

L-DOPA works because it skips the slow step. In Parkinson's disease, giving L-DOPA bypasses tyrosine hydroxylase, and it crosses the blood-brain barrier where dopamine itself cannot.

Diet reaches some transmitters. Tryptophan and tyrosine come from food and compete for the same carrier into the brain, so supply can limit serotonin synthesis.

Recycling saves the cost of making. Most glutamate and the monoamines are recovered after release rather than made anew; acetylcholine is split and its choline taken back.

Transmitters are cheap to make; the identity of a neuron is in its enzymes.

GABA is glutamate with one step more, which is why one enzyme decides whether a cell excites or inhibits.

Questions: What is GABA made from? From glutamate, in a single step catalysed by glutamic acid decarboxylase (GAD). The brain's main brake is built from its main accelerator, so whether a neuron excites or inhibits its targets depends largely on whether it expresses that one enzyme.