Appearance
6.2 — The Neuromuscular Junction
Every voluntary movement you make passes through a gap 20 to 50 nanometres wide between a nerve ending and a muscle fibre. That gap is crossed by a single chemical, acetylcholine, and the whole transaction takes under a millisecond.
It is the most thoroughly understood synapse in the body, largely because it is accessible, uses one transmitter, and is the target of an unusually large number of poisons — snake venom, plant alkaloids, nerve agents, bacterial toxins and several routinely used drugs all act here. Working out how each of them interferes is how the junction was mapped.
The structure
The presynaptic terminal — the swollen end of a motor neuron, packed with mitochondria and with about 300,000 vesicles, each containing roughly 5,000 to 10,000 molecules of acetylcholine.
The synaptic cleft — the gap, 20 to 50 nanometres, containing a basement membrane on which sits the enzyme that destroys acetylcholine.
The motor end plate — the specialised patch of muscle membrane opposite. It is thrown into deep folds, which multiplies its area, and the acetylcholine receptors are concentrated at the tops of the folds at densities of around 10,000 per square micrometre while the voltage-gated sodium channels sit down in the troughs. That arrangement means the transmitter meets receptors immediately and the resulting depolarisation meets sodium channels immediately.
One motor neuron supplies many muscle fibres, but each muscle fibre has exactly one junction, roughly at its midpoint — so the impulse spreads in both directions and reaches both ends simultaneously.
The sequence, step by step
1. The action potential arrives at the nerve terminal.
2. Voltage-gated calcium channels open. Calcium enters the terminal.
3. Calcium triggers vesicle fusion. Vesicles already docked at the membrane fuse with it and release acetylcholine into the cleft. Around 100 to 300 vesicles release per impulse.
4. Acetylcholine diffuses across — which takes under 0.1 milliseconds over that distance — and binds nicotinic acetylcholine receptors.
5. The receptor is itself an ion channel (Chapter 1.8), and it opens when two acetylcholine molecules bind. Sodium enters, potassium leaves, and the net effect is depolarisation of the end plate.
6. That depolarisation triggers an action potential in the muscle membrane, which propagates in both directions and down the T-tubules (Chapter 6.1).
7. Acetylcholinesterase destroys the acetylcholine within about a millisecond, splitting it into choline and acetate. The choline is taken back into the nerve terminal and recycled, which matters because the nerve would otherwise run out.
The safety factor
The junction releases far more transmitter than it needs. The end plate potential produced is roughly three to four times the threshold required to fire the muscle fibre — a safety factor of three to four.
This is why a junction can lose a substantial fraction of its receptors or its transmitter release before anything is noticeable, and it is exactly why myasthenia gravis presents as fatigue rather than as weakness. The first few contractions are fine because the reserve covers the deficit; the reserve runs down with repeated use, and then the muscle fails.
It also means the junction is remarkably reliable in health. Under normal conditions, transmission failure essentially never occurs — every nerve impulse produces a muscle action potential.
Where drugs and poisons act
Every step above is a target, and going through them in order is the clearest way to learn both the physiology and a substantial slice of pharmacology.
Blocking calcium entry — botulinum toxin
Botulinum toxin, from Clostridium botulinum, does not block the channel. It enters the nerve terminal and cleaves the proteins that vesicles need in order to fuse with the membrane. No fusion, no release, no transmission — flaccid paralysis.
It is among the most toxic substances known, with an estimated lethal dose in the region of a nanogram per kilogram. Botulism from contaminated food causes descending paralysis, starting with the eyes and throat and progressing to the diaphragm.
And the same property makes it a widely used medicine. Injected in minute quantities it paralyses a specific muscle for three to six months, until the nerve terminal grows new endings. The medical uses are substantial and predate the cosmetic ones: cervical dystonia, spasticity after stroke or in cerebral palsy, chronic migraine, excessive sweating, overactive bladder, and squint. The cosmetic use is the same mechanism applied to the muscles that crease the forehead.
Infant botulism is the reason honey is not given to babies under one year. Honey can contain botulinum spores, which are harmless to an adult gut but can germinate in an infant's immature gut flora and produce toxin in situ.
Blocking the receptor — curare and the surgical relaxants
Curare, from South American plants, is a competitive antagonist: it occupies the acetylcholine receptor without activating it. Acetylcholine is still released and still present, but it cannot get in. The result is flaccid paralysis with completely intact consciousness and sensation.
That last point is not a technicality. Neuromuscular blockers do not anaesthetise, sedate or relieve pain. A paralysed patient who is inadequately anaesthetised is fully aware and unable to move or signal, and awareness under anaesthesia, though rare, is a recognised and deeply traumatic complication. It is why depth-of-anaesthesia monitoring exists and why blockers are never given without anaesthesia.
Modern non-depolarising blockers — rocuronium, vecuronium, atracurium — work the same way and are used to relax muscles for surgery and to allow a breathing tube to be placed. They are reversed by neostigmine, which blocks acetylcholinesterase so acetylcholine accumulates and outcompetes the drug, or — for rocuronium specifically — by sugammadex, which is a molecule shaped to wrap around the drug and remove it from circulation directly, working within minutes and far more completely.
Suxamethonium works by the opposite trick and it is worth understanding. It binds the receptor and activates it, but it is not broken down by acetylcholinesterase, so the receptor stays open. The membrane depolarises and stays depolarised, which means it cannot fire again. The result is an initial burst of muscle twitching — visible as fasciculations — followed by paralysis. It is used where very fast onset and short duration are needed.
Two of its side effects come directly from that mechanism. The sustained channel opening lets potassium leak out of every muscle in the body, which can cause dangerous hyperkalaemia in patients with burns, crush injury or prolonged immobility, where receptors have multiplied across the muscle surface. And it is one of the triggers of malignant hyperthermia (Chapter 6.1).
Blocking the enzyme — from Alzheimer's drugs to nerve agents
Acetylcholinesterase inhibitors stop acetylcholine being destroyed, so it accumulates and its effect is prolonged and amplified.
In small controlled doses this is therapeutic. Neostigmine and pyridostigmine treat myasthenia gravis. Donepezil and rivastigmine are used in Alzheimer's disease, acting on the same enzyme in the brain.
In large doses it is a chemical weapon. Organophosphate insecticides and nerve agents such as sarin and VX bind the enzyme irreversibly. Acetylcholine accumulates everywhere it is used — at neuromuscular junctions, in the parasympathetic system, and in the brain.
The syndrome is memorable and the mnemonic is used worldwide: DUMBELS — Diarrhoea, Urination, Miosis (constricted pupils), Bronchorrhoea and Bronchospasm, Emesis, Lacrimation, Salivation. Death is usually from bronchial secretions flooding the airway combined with respiratory muscle paralysis.
Treatment has two arms, and both are needed. Atropine blocks the muscarinic receptors, drying up the secretions and reversing the slow heart rate — and the dose required is very large, far beyond ordinary doses, titrated against the chest sounds rather than the heart rate. Pralidoxime reactivates the enzyme by pulling the organophosphate off it, and it must be given early, because after some hours the bond "ages" into a permanent one and the enzyme cannot be recovered. Chapter 23.6.
Blocking transmitter release from outside — venoms
Several snake venoms act here. Alpha-bungarotoxin, from the many-banded krait, binds the acetylcholine receptor almost irreversibly — and because it binds so tightly and specifically, it became the laboratory tool that allowed the receptor to be isolated and identified in the first place. A poison that was used to find its own target.
Beta-bungarotoxin attacks the presynaptic terminal instead. Cobra and krait envenomation causes progressive paralysis starting with drooping eyelids and difficulty swallowing, progressing to respiratory failure. Antivenom plus mechanical ventilation until the effect wears off is the treatment, and with ventilation available the survival rate is high (Chapter 23.9).
Myasthenia gravis
An autoimmune disease in which antibodies attack the acetylcholine receptor. It affects roughly 1 in 5,000 people.
The mechanism has three parts: antibodies block the receptor directly, they cross-link receptors causing the cell to internalise and destroy them, and they activate complement which damages the end plate. The folds of the end plate are flattened and the receptor number falls to around a third of normal.
The safety factor explained above is why the symptom is fatigability. The first contractions have just enough receptors; with repeated use the reserve is exhausted and the muscle fails. So the defining feature is weakness that worsens with use and improves with rest, and it is worse in the evening.
The presentation is characteristic. Around two thirds start with eye symptoms — drooping eyelids and double vision — because the eye muscles have small motor units and fire at high rates, so they exhaust their reserve first. Then bulbar muscles: difficulty chewing, swallowing and speaking, with a nasal voice that deteriorates during a conversation. Then limb weakness, proximal more than distal.
Myasthenic crisis is respiratory failure from weakness of the diaphragm and intercostals, and it is a medical emergency requiring ventilation.
Diagnosis. Antibody testing (anti-acetylcholine receptor antibodies in about 85 percent; anti-MuSK in some of the rest). Repetitive nerve stimulation showing a decreasing response. Single-fibre electromyography. And an ice pack test — placing ice on a drooping eyelid for two minutes improves it, because cooling slows acetylcholinesterase, so more transmitter survives. It costs nothing and is remarkably specific.
Treatment.
- Pyridostigmine — an acetylcholinesterase inhibitor, giving symptomatic improvement within 30 minutes.
- Immunosuppression — steroids, azathioprine, mycophenolate, and newer targeted agents.
- Thymectomy. Around 10 to 15 percent of patients have a thymoma, and many others have an abnormal thymus, and removing it improves the disease in a substantial proportion — a finding that led to the thymus being understood as the site where the autoimmunity is generated (Chapter 13.2). Every newly diagnosed patient has chest imaging to look for a thymoma.
- Plasma exchange or intravenous immunoglobulin in crisis, to remove or neutralise the antibodies quickly.
And a list of drugs to avoid, because many worsen myasthenia by interfering with transmission: aminoglycoside and fluoroquinolone antibiotics, magnesium, beta-blockers, and several others. This list belongs on the patient's record, because giving one of these in an emergency department to someone whose diagnosis was not known has precipitated crises.
Lambert–Eaton myasthenic syndrome is the presynaptic mirror image: antibodies attack the calcium channels in the nerve terminal, so less transmitter is released. The weakness improves briefly with repeated effort, because calcium accumulates in the terminal with sustained activity — the opposite of myasthenia gravis. And it is associated with small cell lung cancer in around half of cases, so its diagnosis triggers a search for a tumour that may not yet be otherwise apparent.
What the next page fixes
The machinery is now complete: nerve to junction to calcium to filament to movement. From here the Part goes through the muscles themselves, region by region. Chapter 6.3 starts with the head and neck — the muscles of facial expression, which are unique in attaching to skin rather than bone, and the muscles of chewing and swallowing, which are the reason a stroke can kill through a chest infection.