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Neurotransmitters of the Autonomic Nervous System (ANS)
Overview
The ANS is traditionally classified based on the primary transmitter released from nerve terminals — acetylcholine (ACh) or norepinephrine (NE). Five key features govern neurotransmitter function: synthesis → storage → release → receptor action → termination.
1. Cholinergic Fibers (Release Acetylcholine)
Fibers that release ACh include:
- All preganglionic fibers (both sympathetic and parasympathetic)
- All parasympathetic postganglionic fibers
- Sympathetic postganglionic fibers to sweat glands
- Somatic motor fibers to skeletal muscle
Steps in Cholinergic Transmission:
| Step | Details |
|---|
| Synthesis | Choline + Acetyl-CoA → ACh, catalysed by choline acetyltransferase (ChAT) in the nerve terminal |
| Storage | ACh stored in small clear synaptic vesicles near the presynaptic membrane; peptide cotransmitters (e.g., VIP, substance P) in large dense-cored vesicles |
| Release | Action potential → voltage-gated Ca²⁺ channels open → intracellular Ca²⁺ rises → vesicles fuse with membrane (via VAMPs + SNAPs, the "fusion proteins") → exocytosis of ACh |
| Receptor Binding | ACh binds nicotinic receptors at ganglia and neuromuscular junction; muscarinic receptors at parasympathetic postganglionic effector organs |
| Termination | Acetylcholinesterase (AChE) rapidly hydrolyses ACh into choline + acetate in the synaptic cleft; choline is recycled back into the terminal |
2. Adrenergic Fibers (Release Norepinephrine)
Fibers that release NE include:
- Most sympathetic postganglionic fibers
- Adrenal medullary chromaffin cells (release epinephrine 80% + NE 20% into the blood)
Steps in Adrenergic Transmission:
| Step | Details |
|---|
| Synthesis | Tyrosine → DOPA (rate-limiting step by tyrosine hydroxylase) → Dopamine → transported into vesicle → Norepinephrine (by dopamine β-hydroxylase inside vesicle). In adrenal medulla, NE → Epinephrine (by PNMT, only in adrenal cells) |
| Storage | NE stored in dense-cored vesicles via VMAT (vesicular monoamine transporter). Blocked by reserpine |
| Release | Action potential → Ca²⁺ influx → vesicle fusion via VAMPs/SNAPs → NE + cotransmitters released into the synapse |
| Receptor Binding | NE/Epi bind α₁, α₂ and β₁, β₂ adrenoceptors on postsynaptic effector cells; α₂ on presynaptic terminal acts as autoreceptor (negative feedback) |
| Termination | (a) Reuptake into terminal via NET (norepinephrine transporter) — primary mechanism; blocked by cocaine, tricyclic antidepressants. (b) Metabolism by MAO (mitochondrial) and COMT (extracellular) |
3. Key Neurotransmitter Summary Table
| Location | Neurotransmitter Released | Receptor Type |
|---|
| All preganglionic → ganglion | ACh | Nicotinic (N_N) |
| Parasympathetic postganglionic → effector | ACh | Muscarinic (M) |
| Sympathetic postganglionic → effector | Norepinephrine | Adrenergic (α, β) |
| Sympathetic → sweat glands | ACh (exception) | Muscarinic |
| Preganglionic → adrenal medulla | ACh | Nicotinic (N_N) |
| Adrenal medulla → blood | Epi (80%) + NE (20%) | Adrenergic (α, β) |
4. Cotransmitters (Non-classic)
Many ANS neurons co-release additional substances alongside the primary transmitter:
- ATP — cotransmitter at many ANS–effector synapses
- Neuropeptide Y (NPY) — co-released with NE; causes prolonged vasoconstriction
- Nitric oxide (NO) — cotransmitter at inhibitory junctions, mediates smooth muscle relaxation
- VIP — cotransmitter in some parasympathetic neurons; vasodilatory
In summary, cholinergic transmission dominates at ganglia and parasympathetic effectors, while adrenergic transmission governs most sympathetic effector organ responses. Both pathways follow the same fundamental steps: synthesis → vesicular storage → Ca²⁺-triggered release → receptor binding → enzymatic/transporter termination.
— Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 148–153; Lippincott Illustrated Reviews: Pharmacology, p. 133–134