Physiology chapters
The neuromuscular junction
How a motor nerve makes a skeletal muscle fibre contract, the end-plate potential, how acetylcholine is removed, and how drugs, toxins and diseases such as myasthenia gravis interfere with transmission.
- At the neuromuscular junction, Ca2+ entry releases acetylcholine, which opens nicotinic receptor channels and produces an end-plate potential.
- The end-plate potential is always large enough to fire the muscle fibre (high safety factor); acetylcholinesterase ends the signal within milliseconds.
- Myasthenia gravis (antibodies to ACh receptors), Lambert-Eaton (antibodies to Ca2+ channels), botulinum toxin and blocking drugs all act here.
On this page
Overview
The neuromuscular junction (NMJ) is the synapse between a motor nerve ending and a skeletal muscle fibre.
Each muscle fibre has one junction, near its middle. Transmission here is reliable: every nerve impulse normally produces a muscle action potential.
Structure
- Nerve terminal: branches lie in grooves on the muscle surface. They contain vesicles of acetylcholine (ACh) and many mitochondria.
- Synaptic cleft with a basal lamina rich in acetylcholinesterase.
- Motor end plate: the folded muscle membrane (subneural clefts), with nicotinic ACh receptors packed at the tops of the folds.
Steps of transmission
- The nerve action potential reaches the terminal.
- Voltage-gated Ca2+ channels open; Ca2+ enters.
- Ca2+ triggers fusion of vesicles and release of ACh.
- ACh binds to nicotinic receptors (two ACh molecules per receptor). The channel opens and lets mainly Na+ in (and some K+ out).
- The end plate depolarises: the end-plate potential (EPP).
- The EPP fires a muscle action potential, which spreads along the fibre.
- Acetylcholinesterase breaks ACh into acetate and choline within a few milliseconds. Choline is taken back into the terminal to make new ACh.
The nicotinic receptor at the NMJ is a ligand-gated cation channel. Its opening is followed by Na+ entry, which produces the end-plate potential.
Miniature end-plate potentials
At rest, single vesicles are released at random. Each causes a tiny depolarisation, a miniature end-plate potential. This shows that ACh is released in packets (quanta).
Safety factor
Normally, each nerve impulse produces an end-plate potential about three times larger than needed to fire the muscle. This is the safety factor. It ensures reliable transmission and is reduced in myasthenia gravis.
Excitation-contraction coupling
How the muscle action potential leads to contraction:
- The action potential spreads along the muscle membrane and down the T tubules.
- Dihydropyridine receptors (voltage sensors) in the T tubule change shape.
- They open ryanodine receptors on the sarcoplasmic reticulum, releasing Ca2+.
- Ca2+ binds troponin C; tropomyosin moves; actin binding sites are uncovered.
- Myosin heads bind actin and pull (cross-bridge cycling), using ATP.
- Ca2+ is pumped back into the sarcoplasmic reticulum, and the muscle relaxes.
In skeletal muscle, the Ca2+ for contraction comes from the sarcoplasmic reticulum, triggered by the voltage sensor in the T tubule.
Drugs and toxins at the NMJ
| Agent | Action | Effect |
|---|---|---|
| Botulinum toxin | Blocks ACh release from the terminal | Flaccid paralysis; used to treat spasm and in cosmetics |
| Curare / tubocurarine, other non-depolarising blockers | Compete with ACh at nicotinic receptors | Flaccid paralysis; reversed by anticholinesterases |
| Suxamethonium (succinylcholine) | Acts like ACh but is not broken down by acetylcholinesterase; causes persistent depolarisation | Brief twitching (fasciculations) then paralysis (depolarising block) |
| Neostigmine, pyridostigmine | Inhibit acetylcholinesterase | More ACh in the cleft; stronger transmission |
| Organophosphates (insecticides, nerve agents) | Irreversibly inhibit acetylcholinesterase | ACh builds up: muscle twitching, then paralysis; plus muscarinic effects |
Anticholinesterases reverse non-depolarising (curare-like) blockers but do not reverse a suxamethonium block; they can make it worse.
Clinical relevance
Myasthenia gravis
How it happens: autoantibodies against the nicotinic ACh receptors at the end plate. Fewer receptors mean smaller end-plate potentials, and the safety factor is lost.
What you see: muscle weakness that is worse after use and better after rest: drooping eyelids, double vision, difficulty swallowing and, in crises, breathing failure. Often linked with thymus abnormalities.
Treatment: anticholinesterases (pyridostigmine) increase ACh in the cleft; immunosuppression; removal of the thymus.
Myasthenia gravis: antibodies against the postsynaptic ACh receptor; weakness gets worse with repeated use.
Lambert-Eaton myasthenic syndrome
How it happens: antibodies against the presynaptic voltage-gated Ca2+ channels, often linked with small-cell lung cancer. Less Ca2+ enters, so less ACh is released.
What you see: weakness of the limbs, especially proximal, with reduced reflexes. Strength improves briefly with repeated effort (Ca2+ builds up in the terminal).
Botulism
How it happens: toxin from Clostridium botulinum in poorly preserved food blocks ACh release.
What you see: descending paralysis, starting with the eyes and throat, and breathing failure.
Organophosphate poisoning
How it happens: common in Pakistan from insecticides; acetylcholinesterase is blocked.
What you see: small pupils, sweating, salivation, diarrhoea, slow heart (muscarinic) plus muscle twitching and weakness (nicotinic).
Expect: the role of Ca2+ in ACh release, the type of receptor at the end plate, the end-plate potential and safety factor, the breakdown of ACh, excitation-contraction coupling, the mechanisms of botulinum toxin, curare and suxamethonium, and the difference between myasthenia gravis and Lambert-Eaton syndrome.
Quick revision
- Ca2+ entry → ACh release → nicotinic receptors → Na+ in → end-plate potential.
- Safety factor: the EPP is about three times threshold.
- Acetylcholinesterase splits ACh into acetate and choline.
- T tubule voltage sensor → ryanodine receptor → Ca2+ from sarcoplasmic reticulum → troponin C.
- Botulinum: blocks release. Curare: competitive block. Suxamethonium: depolarising block.
- Myasthenia: antibodies to ACh receptors; worse with use.
- Lambert-Eaton: antibodies to Ca2+ channels; better with repeated use.
Written by The House Job from standard physiology references (Guyton and Hall Textbook of Medical Physiology; BRS Physiology).
FAQ
Which receptor is found at the motor end plate?
The nicotinic acetylcholine receptor, a ligand-gated cation channel.
What is the end-plate potential?
The local depolarisation of the muscle membrane caused by acetylcholine opening nicotinic receptor channels.
What is the defect in myasthenia gravis?
Antibodies destroy or block acetylcholine receptors at the neuromuscular junction.
How does botulinum toxin cause paralysis?
It prevents the release of acetylcholine from the motor nerve terminal.