Cholinergic system
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Here is a comprehensive overview of the cholinergic system, synthesized from Ganong's, Goodman & Gilman's, Katzung's, and Lippincott's:
The Cholinergic System
1. Overview
The cholinergic system uses acetylcholine (ACh) as its neurotransmitter. It operates at multiple sites:
- Autonomic ganglia (both sympathetic and parasympathetic)
- Parasympathetic postganglionic nerve-effector organ junctions
- Somatic motor nerve-skeletal muscle junctions (neuromuscular junction)
- Select CNS pathways (basal forebrain, striatum, reticular formation)
ACh does not normally circulate in the blood. Its effects are discrete and short-lived because acetylcholinesterase (AChE) at cholinergic nerve endings rapidly degrades it.
2. Synthesis, Storage, Release, and Degradation
The life cycle of ACh involves six steps:
| Step | Event | Key Detail |
|---|---|---|
| 1 | Synthesis | Choline + Acetyl-CoA → ACh, catalyzed by choline acetyltransferase (ChAT). Choline uptake is the rate-limiting step; requires Na⁺-coupled transporter. |
| 2 | Storage | ACh packaged into vesicles by active transport. Vesicles also contain ATP (a cotransmitter) and proteoglycan. |
| 3 | Release | Action potential → voltage-gated Ca²⁺ channels open → Ca²⁺ influx → vesicle fusion → exocytosis. Botulinum toxin blocks release; black widow spider venom causes massive release. |
| 4 | Receptor binding | ACh binds muscarinic or nicotinic receptors on postsynaptic membranes or presynaptic autoreceptors. |
| 5 | Degradation | AChE rapidly cleaves ACh into choline + acetate in the synaptic cleft. |
| 6 | Choline recycling | Choline recaptured by high-affinity Na⁺-coupled transporter back into the neuron; hemicholinium blocks this step. |
- Lippincott Illustrated Reviews: Pharmacology, pp. 145-146
- Goodman & Gilman's Pharmacological Basis of Therapeutics
3. Cholinergic Receptors
ACh acts on two broad families of receptors:
A. Nicotinic Receptors (nAChR) - Ionotropic
- Structure: Pentameric ligand-gated ion channels composed of subunits from 17 known types (α1-10, β1-4, γ, δ). Two ACh molecules must bind simultaneously (one on each α subunit) for efficient channel opening.
- Mechanism: Agonist binding opens Na⁺/K⁺ channels → depolarization + Ca²⁺ influx.
- Subtypes and locations:
| Subtype | Location | Blocked by |
|---|---|---|
| N_N (neuronal, α3β4 dominant) | Autonomic ganglia, adrenal medulla | Hexamethonium |
| N_M (muscle) | Neuromuscular junction | D-tubocurarine (curare) |
| α4β2 | Most abundant in CNS (hippocampus, hypothalamus) | - |
| α7 (homomeric) | CNS and peripheral immune cells | - |
- The α4β2 subtype mediates nicotine addiction via dopamine release in the mesolimbic system.
- The α7 subtype is involved in cognition, pain, and anti-inflammatory signaling (reduces cytokine release from macrophages/microglia).
- Katzung's Basic and Clinical Pharmacology, 16th Ed., pp. 544-552
B. Muscarinic Receptors (mAChR) - Metabotropic (GPCR)
All five subtypes are G protein-coupled receptors (GPCRs). Non-selective antagonists: atropine, scopolamine, ipratropium.
| Subtype | G Protein / Effector | Location | Key Function |
|---|---|---|---|
| M1 | Gq → PLC → IP3/DAG → ↑Ca²⁺ | Cortex, hippocampus, gastric glands | Cognition, gastric acid secretion; M1 KO → impaired forebrain plasticity |
| M2 | Gi/Go → ↓adenylyl cyclase; opens K⁺ channels | Heart (SA/AV node), presynaptic terminals | ↓Heart rate, ↓AV conduction; presynaptic autoreceptor inhibiting ACh release |
| M3 | Gq → PLC → ↑Ca²⁺ | Smooth muscle, glands, eye, hypothalamus | Contraction of smooth muscle, glandular secretion; M3 KO → reduced appetite |
| M4 | Gi/Go → ↓adenylyl cyclase | Striatum, CNS | Modulation of dopamine in striatum |
| M5 | Gq → PLC | CNS, dopaminergic neurons | Modulation of mesolimbic dopamine |
- Agonists: ACh, carbachol, oxotremorine, pilocarpine (M1/M3 selective), cevimeline
- Selective antagonists: pirenzepine (M1), AF-DX 116 (M2), darifenacin (M3)
- Goodman & Gilman's, Table 16-3; Ganong's, p. 267
4. Autonomic Ganglionic Transmission
At autonomic ganglia, ACh produces two types of postsynaptic potentials in postganglionic neurons:
-
Fast EPSP - via nicotinic (N_N) receptors → rapid depolarization, action potential generation
-
Slow EPSP - via muscarinic (M1) receptors on the postganglionic neuron → modulates and regulates ganglionic transmission
-
Ganong's Review of Medical Physiology, 26th Ed., p. 267
5. Peripheral Parasympathetic Effects (via M2 and M3)
| Organ | Cholinergic (Parasympathetic) Effect |
|---|---|
| Heart (SA node) | Decreased heart rate (M2 → ↑K⁺ conductance → hyperpolarization) |
| Heart (AV node) | Decreased conduction velocity |
| Heart (atria) | Decreased contractility |
| Sphincter muscle of iris | Contraction → miosis |
| Ciliary muscle | Contraction → accommodation for near vision |
| Bronchial smooth muscle | Bronchoconstriction |
| GI smooth muscle | Increased motility and secretion |
| Bladder detrusor | Contraction (urination) |
| Salivary/lacrimal glands | Increased secretion |
| Blood vessels (endothelium) | Vasodilation via NO release |
- Ganong's Review of Medical Physiology, Table 13-1
6. CNS Cholinergic Pathways
Eight major ACh-containing nuclei in the CNS project diffusely throughout the brain:
- Basal nucleus of Meynert → cortex (memory, cognition)
- Medial septal nucleus → hippocampus
- Reticular formation → arousal, attention
- Neostriatum → motor control, reward
Clinical relevance:
-
Loss of cholinergic neurons in these pathways is the hallmark of Alzheimer's disease (associated with marked reductions in ChAT and ACh concentrations)
-
Nicotinic receptor activation in the CNS (especially α4β2) promotes dopamine release in the mesolimbic system → basis of nicotine's addictive and alerting effects
-
Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 592
7. Pharmacological Modulation Summary
| Target | Drug Class | Examples | Effect |
|---|---|---|---|
| AChE | Anticholinesterases | Neostigmine, physostigmine, organophosphates | ↑ACh (indirect agonism) |
| Muscarinic receptors | Muscarinic agonists | Pilocarpine, bethanechol, carbachol | Direct cholinomimetic |
| Muscarinic receptors | Muscarinic antagonists | Atropine, scopolamine, ipratropium | Block parasympathetic effects |
| Nicotinic (NMJ) | NMJ blockers | D-tubocurarine, succinylcholine | Muscle relaxation |
| Nicotinic (ganglia) | Ganglion blockers | Hexamethonium | ↓Autonomic ganglionic transmission |
| ACh synthesis | Hemicholinium | Hemicholinium-3 | Blocks choline reuptake |
| ACh release | Botulinum toxin | Botox | Prevents ACh exocytosis |
| ACh vesicle loading | Vesamicol | Vesamicol | Blocks vesicular ACh transport |
Key Clinical Correlates
- Organophosphate poisoning / nerve agents: Irreversible AChE inhibition → SLUDGE syndrome (Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis) + nicotinic effects (muscle fasciculations, paralysis). Treat with atropine + pralidoxime.
- Myasthenia gravis: Autoantibodies against N_M receptors at the NMJ → muscle weakness. AChE inhibitors (pyridostigmine) are first-line.
- Alzheimer's disease: Cholinergic deficit treated with AChE inhibitors (donepezil, rivastigmine, galantamine).
- Glaucoma: Pilocarpine (M3 agonist) contracts ciliary muscle and sphincter pupillae → opens trabecular meshwork → ↓intraocular pressure.
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