Neuromuscular junction
Synapse and neuromuscular junction: transmission, drugs, toxins and myasthenia
How chemical synapses and the neuromuscular junction transmit signals, and how drugs, toxins and diseases act at each step, for FCPS Part 1. Covers synaptic delay, EPSPs, IPSPs, presynaptic inhibition, blockers, myasthenia and Lambert–Eaton.
Steps of chemical transmission
- An action potential reaches the presynaptic terminal.
- Voltage-gated Ca²⁺ channels open and calcium enters. Calcium is the essential trigger: without it there is no release.
- Vesicles dock and fuse with the membrane through SNARE proteins (synaptobrevin on the vesicle; syntaxin and SNAP-25 on the membrane) and release transmitter by exocytosis.
- Transmitter diffuses across the 20–40 nm cleft and binds postsynaptic receptors, opening ion channels (ionotropic) or activating G proteins (metabotropic).
- Action ends by enzymatic breakdown (acetylcholinesterase), reuptake (noradrenaline, dopamine, serotonin, GABA, glutamate) or diffusion away.
Synaptic delay and one-way conduction
- Each synapse adds a delay of about 0.5 ms, the time needed for calcium entry, vesicle fusion, release, diffusion and receptor binding. Counting delays tells how many synapses a reflex uses: the stretch reflex is monosynaptic; the withdrawal (flexor) reflex is polysynaptic.
- Transmission is one-way because vesicles and release machinery exist only in the presynaptic terminal and receptors only on the postsynaptic membrane.
- Electrical synapses (gap junctions) are almost instantaneous and can conduct in both directions; they couple cardiac muscle and single-unit (visceral) smooth muscle.
| Feature | Chemical synapse | Electrical synapse |
|---|---|---|
| Delay | About 0.5 ms | Almost none |
| Direction | One-way | Two-way |
| Mechanism | Transmitter and receptor | Gap junction ion flow |
| Plasticity, fatigue, drug action | Yes | Little |
| Sites | Most CNS and peripheral synapses | Heart, visceral smooth muscle, some CNS nuclei |
Postsynaptic integration
- EPSP: opening of non-selective cation channels lets Na⁺ in, depolarising the cell (glutamate on AMPA receptors, ACh on nicotinic receptors).
- IPSP: GABA on GABA-A receptors and glycine open chloride channels; Cl⁻ influx hyperpolarises the cell. GABA-B receptors open K⁺ channels through G proteins (K⁺ efflux). Benzodiazepines increase the frequency of GABA-A opening, barbiturates the duration.
- Summation at the axon hillock: temporal (repeated inputs from one terminal) and spatial (inputs from many terminals). The hillock has the lowest threshold and fires first.
- Presynaptic inhibition: an axo-axonal synapse (often GABA) partially depolarises the presynaptic terminal, so fewer Ca²⁺ channels open and less transmitter is released; the postsynaptic membrane potential is unchanged. In the dorsal horn, inhibitory interneurons of the substantia gelatinosa release enkephalin onto incoming pain fibres (C fibres, which synapse mainly in lamina II), reducing substance P and glutamate release; opioids work the same way.
- Seizures follow loss of inhibition: drugs that block GABA-A receptors (picrotoxin, bicuculline, high-dose penicillin, flumazenil in benzodiazepine dependence) or glycine receptors (strychnine) cause convulsions.
- Facilitation (residual calcium), post-tetanic potentiation and long-term potentiation (NMDA receptors) underlie short- and long-term memory.
Neuromuscular junction
- Motor neuron releases acetylcholine onto nicotinic (N_M) receptors concentrated on the crests of junctional folds of the motor end-plate. These are ligand-gated cation channels: Na⁺ in, K⁺ out.
- Each vesicle (quantum) produces a miniature end-plate potential; one impulse releases 100–300 quanta, producing an end-plate potential several times larger than threshold (the safety factor), so every nerve impulse normally triggers a muscle action potential.
- Acetylcholinesterase in the basal lamina hydrolyses ACh within milliseconds; choline is taken back up.
- Cardiac muscle has no neuromuscular junctions; autonomic fibres release transmitter from varicosities.
Drugs and toxins
| Agent | Site | Effect |
|---|---|---|
| Botulinum toxin | Cleaves SNAP-25 in cholinergic terminals | No ACh release: flaccid descending paralysis, dilated pupils |
| Tetanus toxin | Cleaves synaptobrevin in inhibitory interneurons (glycine, GABA) | Spastic paralysis, trismus, opisthotonus |
| α-Latrotoxin (black widow) | Massive ACh release | Spasm, then depletion |
| Aminoglycosides, Mg²⁺ | Reduce Ca²⁺-dependent release | Potentiate blockers; worsen myasthenia |
| Non-depolarising blockers (rocuronium, vecuronium, atracurium) | Competitive antagonists at N_M | Flaccid paralysis; reversed by neostigmine or sugammadex (rocuronium, vecuronium) |
| Suxamethonium | Depolarising agonist, persistent depolarisation | Fasciculations then paralysis; hyperkalaemia; malignant hyperthermia; prolonged in pseudocholinesterase deficiency |
| Anticholinesterases (neostigmine, pyridostigmine, edrophonium) | Inhibit AChE | More ACh in the cleft; treat myasthenia |
| Organophosphates | Irreversible AChE inhibition | Muscarinic and nicotinic excess |
| Hemicholinium | Blocks choline uptake | Depletes ACh |
Diseases of the neuromuscular junction
| Disease | Target | Features |
|---|---|---|
| Myasthenia gravis | Antibodies to postsynaptic AChR (or MuSK) | Fatigable weakness, bilateral ptosis, diplopia, worse by evening; decrement on repetitive stimulation; thymoma or thymic hyperplasia |
| Lambert–Eaton syndrome | Antibodies to presynaptic P/Q voltage-gated Ca²⁺ channels | Proximal weakness that improves with use (increment), autonomic symptoms, reduced reflexes; small cell lung cancer |
| Botulism | Toxin | Descending paralysis, fixed dilated pupils |
- Myasthenia is a type II hypersensitivity: antibodies block, cross-link and internalise receptors and fix complement on the end-plate, so fewer receptors respond and the safety factor is lost.
- Diagnosis: anti-AChR antibodies; repetitive nerve stimulation; single-fibre EMG; the ice-pack test for ptosis; edrophonium (short-acting anticholinesterase) briefly improves strength. Pyridostigmine is the symptomatic drug of choice, with steroids, other immunosuppressants and thymectomy.
Exam trap Myasthenia shows a decrement with repeated stimulation; Lambert–Eaton shows an increment.
Key transmitters
| Transmitter | Main sites |
|---|---|
| Acetylcholine | NMJ, all autonomic ganglia, parasympathetic endings, sweat glands, nucleus basalis (memory) |
| Noradrenaline | Most sympathetic postganglionic endings (excitatory transmitter there, acting on α and β1 receptors), locus coeruleus |
| Dopamine | Substantia nigra to caudate and putamen (nigrostriatal), mesolimbic, tuberoinfundibular |
| Serotonin | Raphe nuclei; gut enterochromaffin cells |
| Glutamate | Main excitatory CNS transmitter (AMPA, NMDA) |
| GABA | Main inhibitory transmitter in the brain |
| Glycine | Main inhibitory transmitter in the spinal cord and brainstem |
| Enkephalin, substance P | Dorsal horn pain modulation and transmission |
Remember Calcium in, vesicles out; one direction, half a millisecond per synapse.
Exam trap Tetanus toxin blocks inhibitory interneurons; botulinum blocks release at motor terminals.
How FCPS asks about this
- Why chemical transmission takes 0.5 ms and is one-way: release, diffusion and binding take time; vesicles are only presynaptic and receptors only postsynaptic.
- Ion causing hyperpolarisation with GABA-A: chloride influx.
- Trigger for transmitter release: Ca²⁺ entry through voltage-gated channels.
- Defect in myasthenia gravis: antibodies to postsynaptic nicotinic ACh receptors (type II hypersensitivity); drug of choice pyridostigmine.
- Presynaptic inhibition: reduced Ca²⁺ entry and transmitter release; enkephalin at pain synapses.
- Polysynaptic reflex: withdrawal reflex; the stretch reflex is monosynaptic.
- Nucleus releasing noradrenaline: locus coeruleus.
Test yourself on this topic
5 of the 10 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
What directly causes the end-plate potential at the neuromuscular junction?
Answer: Opening of ligand-gated nicotinic cation channels
Acetylcholine binds nicotinic receptors on the motor end plate. These are ligand-gated channels permeable to sodium and potassium; the net sodium inflow produces a local, graded depolarisation (the end-plate potential). Normally it is large enough to trigger an action potential in neighbouring muscle membrane. Acetylcholinesterase then rapidly ends the signal.
End-plate potential
- ACh on nicotinic receptors
- Ligand-gated Na⁺/K⁺ channel
- Local, graded depolarisation
- Then muscle action potential
- AChE ends it
Remember Nicotinic channel opens, end plate depolarises.
Exam trap The end-plate potential is graded; the muscle action potential is all-or-none.
Why the other options are wrong
- Opening of voltage-gated calcium channels in muscle Excitation–contraction step, after the action potential.
- Closure of potassium channels Not the mechanism.
- Calcium release from the sarcoplasmic reticulum Happens after the muscle action potential.
- Activation of muscarinic receptors Not at skeletal muscle.
After a clean cut of a peripheral nerve with good repair, at about what rate do axons regenerate?
Answer: About 1 mm per day
After transection, the distal axon and myelin undergo Wallerian degeneration (macrophages and Schwann cells clear debris). Schwann cells proliferate and form bands (of Büngner) that guide sprouts from the proximal stump, which grow about 1 mm per day (roughly an inch a month). Recovery is best after neurapraxia (no axon damage) and axonotmesis (axon cut, sheath intact); neurotmesis (whole nerve cut) needs surgical repair and recovery is incomplete. CNS axons regenerate poorly because oligodendrocytes and glial scarring inhibit growth.
Nerve regeneration
- Distal end: Wallerian degeneration
- Guide: Schwann cells (bands of Büngner)
- Rate: ~1 mm/day
- Seddon: neurapraxia, axonotmesis, neurotmesis (needs repair)
Remember One millimetre a day keeps the nerve on its way.
Why the other options are wrong
- About 1 cm per day Too fast.
- About 1 mm per week Too slow.
- About 10 cm per month Too fast.
- They do not regenerate Peripheral axons can regenerate; CNS axons regenerate poorly.
A smoker with a lung mass has proximal leg weakness that improves briefly after repeated effort, a dry mouth and reduced reflexes. Antibodies against which target cause this?
Answer: Presynaptic calcium channels
Lambert–Eaton myasthenic syndrome is often paraneoplastic with small cell lung cancer. Antibodies block P/Q-type voltage-gated calcium channels on the nerve terminal, so less acetylcholine is released. Repeated contraction lets calcium build up, briefly improving strength and reflexes (post-tetanic facilitation). Autonomic features such as a dry mouth are common. Electromyography shows an incremental response.
Lambert–Eaton
- Anti-VGCC (presynaptic)
- Small cell lung cancer
- Improves with repeated effort
- Reduced reflexes, dry mouth
Remember Lambert–Eaton gets better as you go.
Exam trap Search for small cell lung cancer in any new Lambert–Eaton case.
Why the other options are wrong
- Postsynaptic ACh receptors Myasthenia gravis; reflexes normal, worse with use.
- Acetylcholinesterase enzyme Not the target.
- Ryanodine receptors in muscle Malignant hyperthermia gene, not antibodies.
- Myelin of peripheral nerves Demyelinating neuropathy.
GABA acting on GABA-A receptors makes a neuron's membrane potential more negative. Which ion movement causes this hyperpolarisation?
Answer: Chloride influx
Hyperpolarisation results from negative charge entering or positive charge leaving the cell. GABA-A and glycine receptors are chloride channels: chloride moves in and causes an inhibitory postsynaptic potential. Potassium efflux (for example through GABA-B linked channels, and after the action potential) also hyperpolarises. Sodium or calcium influx depolarises.
Hyperpolarisation
- Cl⁻ in (GABA-A, glycine)
- K⁺ out (after AP, GABA-B)
- Na⁺ or Ca²⁺ in: depolarise
- IPSP = inhibitory
Remember Chloride in or potassium out makes the cell more negative.
Exam trap Benzodiazepines increase how often the GABA-A chloride channel opens.
Why the other options are wrong
- Sodium influx Depolarises.
- Calcium influx Depolarises.
- Potassium influx Potassium normally moves out, not in.
- Chloride efflux Would depolarise.
What happens at the neuromuscular junction when an action potential reaches the motor nerve terminal?
Answer: Ca²⁺ channels open; ACh released
Depolarisation opens presynaptic voltage-gated Ca²⁺ channels; Ca²⁺ triggers vesicle fusion (SNARE proteins) and ACh release. ACh binds nicotinic receptors on the end plate, producing the end-plate potential. Acetylcholinesterase ends the signal. Lambert–Eaton antibodies target Ca²⁺ channels; botulinum toxin cleaves SNAREs; myasthenia antibodies target ACh receptors.
Neuromuscular junction
- Ca²⁺ in → ACh release (SNARE)
- Nicotinic receptors on end plate
- Lambert–Eaton: Ca²⁺ channel; MG: ACh receptor; botulinum: SNARE
Remember Calcium opens the ACh gates.
Why the other options are wrong
- Na⁺ enters to release noradrenaline ACh, not noradrenaline.
- Potassium enters the terminal Not the mechanism.
- ACh is broken down before release It is broken down after release.
- Calcium leaves the terminal Calcium enters.
Where this sits in the CPSP syllabus
- Paper 1: Cell, nerve and muscle, Synapse, neuromuscular junction and transmission
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