Neuromuscular junction

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Physiology • Muscles

NEUROMUSCULAR JUNCTION

Structure, neuromuscular transmission, neuromuscular blockers, motor unit and disorders of neuromuscular junction.

1. DEFINITION AND STRUCTURE

Neuromuscular Junction

Neuromuscular junction → junction between the terminal branch of nerve fiber and muscle fiber.
Skeletal muscle fibers are innervated by motor nerve fibers.
Each nerve fiber (axon) divides into many terminal branches.
Each terminal branch innervates one muscle fiber through the neuromuscular junction.

Axon Terminal and Motor Endplate

Terminal branch of nerve fiber → called axon terminal.
When the axon comes close to muscle fiber, it loses its myelin sheath.
The axis cylinder of this portion of axon is expanded like a bulb → called motor endplate.

Axon Terminal Contains

Mitochondria
Synaptic vesicles
Synaptic vesicles contain the neurotransmitter acetylcholine.
Acetylcholine is synthesized by mitochondria present in axon terminal and stored in vesicles.
Mitochondria contain ATP, which is the source of energy for synthesis of acetylcholine.

Synaptic Trough or Synaptic Gutter

Motor endplate invaginates inside the muscle fiber.
This forms a depression called synaptic trough or synaptic gutter.
Membrane of muscle fiber below the motor endplate is thickened.

Synaptic Cleft

Membrane of nerve ending → presynaptic membrane.
Membrane of muscle fiber → postsynaptic membrane.
Space between these two membranes → synaptic cleft.
Synaptic cleft contains basal lamina.
Basal lamina is a thin layer of spongy matrix through which extracellular fluid diffuses.
A large quantity of the enzyme acetylcholinesterase is attached to the matrix of basal lamina.

Subneural Clefts

Postsynaptic membrane is the membrane of muscle fiber.
It is thrown into numerous folds called subneural clefts.
Postsynaptic membrane contains receptors called nicotinic acetylcholine receptors.

2. NEUROMUSCULAR TRANSMISSION

Neuromuscular transmission → transfer of information from motor nerve ending to muscle fiber through neuromuscular junction.
It is the mechanism by which motor nerve impulses initiate muscle contraction.

Events of Neuromuscular Transmission

Release of acetylcholine.
Action of acetylcholine.
Development of endplate potential.
Development of miniature endplate potential.
Destruction of acetylcholine.

1. RELEASE OF ACETYLCHOLINE

When action potential reaches axon terminal:
- It opens voltage-gated calcium channels in membrane of axon terminal.
Calcium ions enter the axon terminal from extracellular fluid.
Calcium causes bursting of synaptic vesicles.
Acetylcholine is released from vesicles and diffuses through the presynaptic membrane.
Acetylcholine enters the synaptic cleft by exocytosis.
Each vesicle contains about 10,000 acetylcholine molecules.
At a time, about 300 vesicles open and release acetylcholine.

2. ACTION OF ACETYLCHOLINE

After entering synaptic cleft, acetylcholine molecules bind with nicotinic receptors present in postsynaptic membrane.
This forms an acetylcholine-receptor complex.
The complex opens the ligand-gated sodium channels in postsynaptic membrane.
Sodium ions from extracellular fluid enter the neuromuscular junction through these channels.
Sodium ions produce an electrical potential called endplate potential.

3. DEVELOPMENT OF ENDPLATE POTENTIAL

Endplate potential → change in resting membrane potential when an impulse reaches the neuromuscular junction.
Resting membrane potential at neuromuscular junction is −90 mV.
When sodium ions enter inside, slight depolarization occurs up to −60 mV.
This is called endplate potential.

Significance of Endplate Potential

Endplate potential is non-propagative.
It causes development of action potential in the muscle fiber.

Properties of Endplate Potential

Endplate potential is a graded potential.
It is not an action potential.

4. DEVELOPMENT OF MINIATURE ENDPLATE POTENTIAL

Miniature endplate potential → a weak endplate potential in neuromuscular junction that is developed by release of a small quantity of acetylcholine from axon terminal.
Each quantity of neurotransmitter produces a weak miniature endplate potential.
Amplitude of this potential is only up to 0.5 mV.
Miniature endplate potential cannot produce action potential in the muscle.
When more and more acetylcholine is released continuously, miniature endplate potentials are added together.
Finally, they produce endplate potential resulting in action potential in the muscle.

5. DESTRUCTION OF ACETYLCHOLINE

Acetylcholine released into the synaptic cleft is destroyed very quickly within 1 millisecond by the enzyme acetylcholinesterase.
However, acetylcholine is so potent that even this short duration of 1 millisecond is sufficient to excite the muscle fiber.

Significance of Destruction of Acetylcholine

Rapid destruction of acetylcholine is functionally significant because:
It prevents repeated excitation of muscle fiber.
It allows the muscle to relax.

Reuptake Process

Reuptake → process in neuromuscular junction by which a degraded product of neurotransmitter re-enters the presynaptic axon terminal where it is reused.
Acetylcholinesterase splits acetylcholine into:
- Inactive choline
- Acetate
Choline is taken back into axon terminal from synaptic cleft by reuptake process.
It is reused in synaptic vesicle to form new acetylcholine.

3. NEUROMUSCULAR BLOCKERS

Neuromuscular blockers → drugs which can prevent transmission of impulses from nerve fiber to muscle fiber through neuromuscular junction.
The following are the neuromuscular blockers commonly used in surgery and research.

1. CURARE

Curare prevents neuromuscular transmission by combining with acetylcholine receptors.
Therefore, acetylcholine cannot combine with the receptors.
Endplate potential cannot develop.
Since curare blocks neuromuscular transmission by acting on acetylcholine receptors, it is called a receptor blocker.

2. BUNGAROTOXIN

Bungarotoxin is a toxin from the venom of deadly snakes.
It affects neuromuscular transmission by blocking the acetylcholine receptors.

3. SUCCINYLCHOLINE AND CARBAMYLCHOLINE

Both drugs block neuromuscular transmission by acting like acetylcholine and keeping the muscles in a depolarized state.
These two drugs are not destroyed as quickly as acetylcholine by cholinesterase.
So, they keep muscles in a depolarized state for a long time.

4. BOTULINUM TOXIN

Botulinum toxin is derived from the bacteria Clostridium botulinum.
It prevents release of acetylcholine from axon terminal in the neuromuscular junction.

4. DRUGS STIMULATING NEUROMUSCULAR JUNCTION

Neuromuscular junction can be stimulated by drugs called cholinesterase inhibitors.
Such drugs inactivate the enzyme acetylcholinesterase.
Acetylcholine is not hydrolyzed, leading to repeated stimulation and continuous contraction of the muscle.

Common Cholinesterase Inhibitors

Donepezil
Rivastigmine
Galantamine

5. MOTOR UNIT

Definition

One single motor neuron, its axon terminals and the muscle fibers innervated by it together are called a motor unit.
Each motor neuron activates a group of muscle fibers through its axon terminals.
Stimulation of a motor neuron causes contraction of all muscle fibers innervated by that neuron.

Number of Muscle Fibers in Motor Unit

Number of muscle fibers in each motor unit varies depending upon the functions of the muscles.

Muscles Concerned With Fine Movements

Number of muscle fibers is small in motor units of muscles concerned with fine, graded and precise movements.

Examples

Muscle	Muscle fibers per motor unit
Laryngeal muscles	2 to 3
Pharyngeal muscles	2 to 6
Ocular muscles	3 to 6

Muscles Concerned With Crude Movements

Muscles concerned with crude or coarse movements have motor units with large number of muscle fibers.
There are about 120 to 165 muscle fibers in each motor unit in these muscles.

Examples

Leg muscles.
Back muscles.

6. APPLIED PHYSIOLOGY: MYASTHENIA GRAVIS

Myasthenia gravis is an autoimmune disease of neuromuscular junction caused by antibodies to cholinergic receptors.
It is characterized by grave weakness of muscle due to the inability of neuromuscular junction to transmit impulses from nerve to muscle.
It is serious and sometimes a fatal disease.

Causes of Myasthenia Gravis

Myasthenia gravis is caused by development of autoantibodies (IgG autoantibodies) against receptors of acetylcholine.
Such antibodies:
- Prevent binding of acetylcholine with its receptors, or
- Destroy the receptors.
Therefore, though acetylcholine release is normal, it cannot execute its action.

Muscles More Susceptible for Myasthenia Gravis

Muscles of neck.
Muscles of limbs.
Muscles of eyeballs.
Muscles responsible for:
- Eyelid movements
- Chewing
- Swallowing
- Speech
- Respiration

Common Symptoms of Myasthenia Gravis

Slow and weak muscular contraction because of defective neuromuscular activity.
Inability to maintain prolonged contraction of skeletal muscle.
Quick fatigability when the patient attempts repeated muscular contractions.
Weakness and fatigability of arms and legs.
Double vision and droopy eyelids due to weakness of ocular muscles.
Difficulty in swallowing due to weakness of throat muscles.
Difficulty in speech due to weakness of muscles of speech.

In severe conditions, paralysis of muscles occurs.
Patient dies mostly due to paralysis of respiratory muscles.

7. LAMBERT-EATON MYASTHENIC SYNDROME

Lambert-Eaton myasthenic syndrome is also an autoimmune disorder of neuromuscular junction.

Cause of Lambert-Eaton Myasthenic Syndrome

This syndrome is caused by development of antibodies against calcium channel in the nerve terminal.
This results in reduction in the release of quanta of acetylcholine.

Common Symptoms of Lambert-Eaton Myasthenic Syndrome

This disease is commonly associated with carcinoma.
Therefore, it is also called carcinomatous myopathy.
This disease is characterized by several features of myasthenia gravis.
In addition, patients have:
- Blurred vision
- Dry mouth