Acetylcholine life cycle: synthesis, storage, release and breakdown
Acetylcholine is made, stored, released and broken down in order, and each step has its own enzyme, transporter or trigger.
Remember
Acetylcholine is made in the nerve ending, packed into vesicles, released when calcium enters, and broken down by an enzyme in the synaptic cleft (the tiny gap between a nerve ending and its target), so each step can fail independently.
Inside the nerve ending, the enzyme choline acetyltransferase (ChAT) joins choline to acetyl-CoA to make acetylcholine (ACh). Choline is a small molecule that the nerve ending recovers from the synaptic cleft, and acetyl-CoA is the cell's carrier of acetyl groups. Only cholinergic neurones (neurones that release ACh) contain ChAT, so the enzyme is also used as a marker for them.
Newly made ACh sits free in the cytoplasm until the vesicular acetylcholine transporter (VAChT), a protein in the wall of the synaptic vesicles, loads it into them. Each vesicle then holds a concentrated, ready-to-release packet called a quantum.
When an action potential reaches the nerve ending, depolarisation opens calcium channels in its membrane, and calcium flows in. That calcium entry is the direct trigger for release. Calcium engages the SNARE proteins, a set of proteins that draw the vesicle membrane and the cell membrane together, so that they fuse, and the vesicle empties its ACh into the cleft by exocytosis.
Acetylcholinesterase (AChE) in the cleft hydrolyses ACh, meaning it splits ACh with water, into acetate and choline. This happens rapidly, so each nerve impulse produces a brief signal. The ACh itself is not taken back intact: high-affinity choline transport returns the choline to the nerve ending, where it is reused to make fresh ACh.
Experimental tools show how the steps differ: vesamicol blocks VAChT, so vesicles cannot be filled; hemicholinium limits choline uptake, so synthesis is limited; and botulinum toxin cuts SNARE proteins, so filled vesicles cannot fuse.
Key facts
- Synthesis
- choline acetyltransferase joins choline to acetyl-CoA to make ACh in the nerve ending.
- Storage
- VAChT loads ACh from the cytoplasm into synaptic vesicles, creating the releasable pool.
- Release
- calcium entry through channels in the nerve ending membrane is the direct trigger, and SNARE proteins fuse the vesicle with the membrane.
- Breakdown
- acetylcholinesterase hydrolyses ACh to acetate and choline within the cleft.
- Recycling
- the choline is carried back into the nerve ending by the high-affinity choline transporter and reused.
- Localising a fault
- if natural transmission fails but a directly applied receptor agonist still produces a response in the target cell, the receptors and the cell are working, which places the defect before them, earlier in the chain.
Exam traps
- Choline acetyltransferase does not use free acetate as its acetyl donor: it uses acetyl-CoA, whereas free acetate is a product of acetylcholinesterase breakdown.
- Intact acetylcholine is not taken back up into the nerve ending. It is broken down in the cleft, and only choline is taken back to make new acetylcholine.
- Potassium leaving the nerve ending through its channels restores the resting voltage after an impulse rather than triggering vesicle fusion, which depends on calcium entry.
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