Autonomic Nerve Terminals: Synthesis, Release & Reuptake
Follow ACh and norepinephrine from synthesis to breakdown, and every drug that intercepts them
Two Terminals, One Blueprint
Cholinergic and noradrenergic terminals run the same sequence: take up a precursor, synthesize the transmitter, package it into vesicles, release it by Ca2+-dependent exocytosis, and terminate its action. Nearly every step has a drug or toxin aimed at it, which is why the nerve terminal is such a rich source of exam questions.
| Step | Cholinergic | Noradrenergic |
|---|---|---|
| Rate-limiting step | Choline uptake (hemicholinium) | Tyrosine hydroxylase (metyrosine) |
| Synthesis | Choline acetyltransferase in cytoplasm | TH and DOPA decarboxylase in cytoplasm; DBH inside vesicle |
| Vesicular transporter | VAChT (vesamicol) | VMAT (reserpine) |
| Release | Ca2+/SNARE exocytosis (botulinum toxin blocks; α-latrotoxin floods) | Ca2+ exocytosis (guanethidine, bretylium, α2 agonists reduce; amphetamine, tyramine displace) |
| Termination | Hydrolysis by AChE | Reuptake by NET (cocaine, TCAs block), then MAO and COMT |
The Cholinergic Terminal
Synthesis. Choline enters through a Na+-dependent, high-affinity choline transporter; this is the rate-limiting step and is blocked by hemicholinium. Choline acetyltransferase then joins choline to acetyl-CoA from mitochondria, forming ACh in the cytoplasm.
Storage and release. The vesicular ACh transporter, an H+ antiporter driven by the vesicle's proton gradient, loads ACh and is blocked by vesamicol. An action potential opens voltage-gated Ca2+ channels; Ca2+ binds synaptotagmin and triggers fusion through the SNARE complex (synaptobrevin on the vesicle, syntaxin and SNAP-25 on the membrane). Less Ca2+ entry means less release: Lambert–Eaton antibodies against P/Q-type channels, hypermagnesemia, and aminoglycosides all weaken transmission.
Toxins. Botulinum toxin is a zinc protease that cleaves SNARE proteins, preventing ACh release at the neuromuscular junction and autonomic synapses: symmetric descending flaccid paralysis with diplopia, dysphagia, dilated poorly reactive pupils, dry mouth, constipation, and urinary retention. Tetanus toxin also cleaves synaptobrevin but acts in inhibitory spinal interneurons, blocking GABA and glycine release and causing spastic paralysis. Black widow α-latrotoxin does the opposite of botulinum toxin: it forms cation pores and forces massive exocytosis of ACh and NE until stores are exhausted, producing painful cramps, abdominal rigidity, sweating, tachycardia, and hypertension.
Termination. Acetylcholinesterase in the cleft hydrolyzes ACh to choline and acetate within milliseconds, and much of the choline is recycled. AChE inhibitors such as neostigmine and organophosphates therefore prolong ACh action at every cholinergic synapse they reach; quaternary neostigmine does not enter the CNS.
Catecholamine Synthesis and Storage
- Tyrosine → L-DOPATyrosine hydroxylase, the rate-limiting step (BH4 cofactor); inhibited by metyrosine.
- L-DOPA → dopamineDOPA decarboxylase (vitamin B6) in the cytoplasm; carbidopa inhibits it outside the brain.
- Vesicular uptakeVMAT pumps dopamine into vesicles; reserpine blocks it irreversibly.
- Dopamine → norepinephrineDopamine β-hydroxylase (copper, vitamin C) inside the vesicle.
- Norepinephrine → epinephrinePNMT in adrenal chromaffin cells, induced by cortisol.
Metyrosine. By inhibiting tyrosine hydroxylase it lowers catecholamine output in pheochromocytoma, before surgery or for inoperable tumors, alongside α-blockade with phenoxybenzamine (α-blockade always precedes β-blockade).
Reserpine. Irreversible binding to VMAT leaves dopamine, NE, and serotonin in the cytoplasm, where MAO destroys them; stores stay depleted for days to weeks until new VMAT is synthesized. Sedation, depression, and nasal congestion follow. Tetrabenazine, a reversible VMAT2 inhibitor, is used for Huntington chorea.
Where each amine ends. Because dopamine β-hydroxylase lives inside vesicles, NE is made only after vesicular uptake; dopaminergic neurons lack the enzyme and release dopamine itself. In the adrenal medulla, NE leaves the vesicle, is methylated by PNMT, and is re-stored as epinephrine. Cortisol-rich blood flowing from the cortex through the medulla induces PNMT, so about 80% of medullary output is epinephrine, whereas extra-adrenal paragangliomas, lacking that cortisol exposure, secrete mainly NE.
Release, Reuptake, and Breakdown
| Mechanism | Drugs | Net effect |
|---|---|---|
| Deplete vesicles | Reserpine | ↓NE release; tyramine ineffective |
| Block release | Guanethidine, bretylium | ↓Sympathetic tone; both need NET to enter |
| α2 autoreceptor agonism | Clonidine, guanfacine; α-methyldopa (via α-methyl-NE) | ↓Sympathetic outflow, mainly central |
| Displace NE | Amphetamine, ephedrine, tyramine | ↑NE release; tachyphylaxis |
| Block reuptake | Cocaine, TCAs, SNRIs | ↑Synaptic NE |
| Block degradation | MAO inhibitors (phenelzine, tranylcypromine); COMT inhibitor entacapone | ↑Amine levels; tyramine crisis with MAO inhibitors |
Release. Ca2+ entry triggers exocytosis of NE together with ATP, chromogranins, and dopamine β-hydroxylase. Presynaptic α2 autoreceptors (Gi, ↓cAMP) provide negative feedback; α2 antagonists such as yohimbine and mirtazapine increase release.
Indirect sympathomimetics. Amphetamine, ephedrine, and tyramine are taken up by NET, displace NE from vesicles, and make NE leak out through reversed NET. Ephedrine also stimulates receptors directly. Because they depend on a releasable pool, repeated doses lose effect (tachyphylaxis). Dietary tyramine is normally destroyed by MAO-A in the gut wall and liver; MAO inhibitors let it reach nerve terminals and provoke a hypertensive crisis.
Reuptake. The norepinephrine transporter (uptake 1) recaptures most released NE for re-storage or degradation. Cocaine, TCAs, and SNRIs block NET, so NE lingers: tachycardia, hypertension, mydriasis, and with cocaine, vasospasm. Cocaine also blocks dopamine and serotonin transporters. Guanethidine also needs NET to enter the terminal, so TCAs and cocaine abolish its antihypertensive effect.
Breakdown. Monoamine oxidase (on neuronal mitochondria) and catechol-O-methyltransferase (in liver, kidney, and adrenal chromaffin cells) degrade catecholamines. COMT converts NE to normetanephrine and epinephrine to metanephrine; the combined MAO and COMT pathways end in vanillylmandelic acid (VMA), and dopamine ends as homovanillic acid (HVA). Plasma free or urine fractionated metanephrines are the preferred tests for pheochromocytoma, while urine VMA and HVA are elevated in neuroblastoma.
Applying the Map: Pretreatment Puzzles and Exceptions
Tyramine versus direct agonists. Tyramine raises blood pressure only by entering through NET and displacing vesicular NE. Reserpine pretreatment empties the vesicles and cocaine pretreatment blocks entry, so either abolishes tyramine's pressor effect. Direct agonists still work: NE and epinephrine responses are enhanced after cocaine because reuptake no longer clears them, and after chronic reserpine because depleted tissues upregulate their receptors.
Drugs that must be carried in by NET (tyramine, amphetamine, guanethidine) lose their effect when NET is blocked; drugs that need full vesicles (tyramine, amphetamine) lose it after reserpine.
- Sweat glands. Eccrine glands are innervated by sympathetic postganglionic fibers that release ACh onto M3 muscarinic receptors, so atropine causes hot, dry skin and hyperthermia.
- Adrenal medulla. Chromaffin cells receive preganglionic sympathetic fibers directly; ACh acts on NN nicotinic receptors, and the cells, acting as modified postganglionic neurons, secrete epinephrine and NE into the blood.
- Renal vasculature. D1 receptors on renal and splanchnic arterioles cause vasodilation; low-dose dopamine and the selective D1 agonist fenoldopam act here.