Neuromuscular Junction

Many people know that any movement performed by the body are regulated by the nervous system. But most of them do not know the exact mechanism of how this happens. They are unaware of the connection between the nervous system and the muscular system.

The neuromuscular junction, as the name indicates, acts as a bridge between the nervous system and the muscular system. It is a microstructure through which the process of contraction is initiated or halted in the muscles by the neurons. Any changes in the neuromuscular junction can result in impaired contractions of the skeletal muscles.

In this article, we will study in detail the structure of the neuromuscular junction, the mechanisms how it initiates the mechanism of contraction, the drugs acting on it as well as its clinical significance. By the end of this article, you will be able to understand the process of how contraction is initiated by the neuromuscular junction.

Structure

The neuromuscular junction is a chemical synapse between the motor neuron and the skeletal muscle fiber. It consists of a presynaptic terminal, synaptic cleft, and a postsynaptic membrane or cell. 

Presynaptic Terminal

In case of neuromuscular junction, the presynaptic terminal is an axonal terminal of a motor neuron. The axonal terminal contains a number of synaptic vesicles. These vesicles contain the neurotransmitters that are released upon receiving a nerve impulse.

The presynaptic terminal also has calcium channels. These channels are voltage-gated calcium channels which open when a nerve impulse reaches the presynaptic axonal terminal.

Synaptic Cleft

It is the space between the presynaptic terminal and the postsynaptic cell. It is roughly the size of 30 nm. The synaptic cleft allows the neurotransmitters to diffuse and reach the other side of the synapse or the neuromuscular junction. It also contains enzymes for the degradation of the excess or extra neurotransmitters.

Post Synaptic Cell or Membrane 

The postsynaptic cell in case of neuromuscular junction is the skeletal muscle fiber. The motor neurons make synapse on the sarcolemma or membrane of the skeletal muscle fibers.

At the neuromuscular junction, the sarcolemma of the skeletal muscle shows a number of invaginations called postjunctional folds. These folds greatly increase the surface area for the neurotransmitters to act.

The walls of these folds have acetylcholine receptors. These receptors are the most important functional part of the neuromuscular junction. A brief detail of these receptors is given below.

Acetylcholine Receptors

Acetylcholine is the neurotransmitter used in neuromuscular junction. The acetylcholine receptors are present in the walls of postjunctional folds. These receptors are also called cholinergic receptors. The receptor can also be activated by nicotine, thus called nicotinic receptors.

The acetylcholine receptors are the ionotropic receptors linked to ion channels. It is made up of two α, one β, one ɛ, and one δ subunit. The acetylcholine binds to the alpha subunit. When a single acetylcholine molecule binds to the alpha subunit, it induces a conformational change resulting in the increased affinity of the second subunit.

When both the subunits are occupied by acetylcholine, it results in the opening of the cation channels, resulting in the inward diffusion of sodium and potassium ions.

Mechanism of Contraction

When a nerve impulse reaches the presynaptic axonal terminal, it causes depolarization. As a result, the voltage-gated calcium channels open. The calcium ions from the surrounding environment diffuse into the presynaptic axon.

These calcium ions activate the SNARE proteins. These proteins mediate the fusion of synaptic vesicles to the cell membrane of the neuron, resulting in the release of acetylcholine into the synaptic cleft.

Once the acetylcholine is released into the synaptic cleft, it diffuses across the synaptic cleft and binds to the acetylcholine receptors. This results in the opening of the cation channels. These channels are open to both sodium and potassium ions.

As the concentration of sodium ions is higher in the extracellular space, the sodium ions enter through these open cation channels. As a result, depolarization of the skeletal muscle ensues.

The depolarization of sarcolemma results in the opening of voltage-gated calcium channels locate on the sarcolemma as well as the membrane of the smooth endoplasmic reticulum.

As the calcium ions enter the cell, it initiates the cycle of skeletal muscle contraction. The actin-myosin bridges are formed, and the result in contraction od the skeletal muscles.

Once the acetylcholine is released into the synaptic cleft, it has a very short half-life. It is immediately metabolized by the acetylcholinesterase to its metabolites. The choline thus formed is taken up by the presynaptic neurons. The metabolism of acetylcholine into its metabolites results in the elimination of all of its effects and the muscle contraction stops.

Drugs Acting on the Neuromuscular Junction

The normal mechanism and function of the neuromuscular junction is affected by the following drugs.

Cholinergic Drugs

These drugs increase the amount of acetylcholine in the synaptic cleft. They are of two types, direct-acting and indirect-acting cholinergic drugs.

Direct Acting Drugs

These drugs increase the amount of acetylcholine by acting as its precursor. These include bethanechol, methacholine, etc.

Indirect Acting Drugs

These are the inhibitors of acetylcholinesterase enzyme. They inhibit the metabolism of acetylcholine, thus resulting in an increased amount of acetylcholine at the synaptic cleft. These drugs include neostigmine, physostigmine, etc.

Neuromuscular Blockers

These are the antagonists of nicotinic acetylcholine receptors present at the neuromuscular junctions. The blockade of these receptors results in relaxing of skeletal muscles. These drugs are used as skeletal muscle relaxants.

They are further divided into two types, non-depolarizing and non-depolarizing. 

Non-depolarizing Drugs

These drugs are the antagonists of nicotinic receptors. They block the receptors and prevent depolarization, thus resulting in the relaxation of skeletal muscle. These drugs have little side effects and are more commonly used as compared to the depolarizing drugs. These include atracurium, tubocurarine, etc.

Depolarizing Drugs

These drugs are powerful agonists of the nicotinic receptors. They cause excessive depolarization, that cannot be reversed. The prolonged depolarization causes A1 block, resulting in relaxation of skeletal muscles. These include suxamethonium and other drugs.

Clinical Significance

The important clinical conditions associated with the neuromuscular junction are as follows.

Myasthenia Gravis

It is an autoimmune disease in which antibodies are formed against the acetylcholine receptors. As a result, the neuromuscular junction is unable to initiate the contraction of skeletal muscles.

It results in varying degrees of muscle weakness. The most commonly affected muscles include the muscle of eyes, face and the pharynx that assist in swallowing.

Lambert-Eaton Syndrome

It is another autoimmune disease of the neuromuscular junction. However, it affects the presynaptic neurons. In this disease, antibodies are formed against the voltage-gated calcium channels present on the presynaptic neurons. A

s a result, the nerve impulse reaching the presynaptic terminal fails to release the neurotransmitter into the synaptic cleft. The muscles are unable to contract. It also causes varying degrees of skeletal muscle weakness.

The most commonly affected muscles include those of legs and arms. The person feels difficulty in walking, climbing stairs, etc.

Neuromyotonia

This disease of the neuromuscular junction results in hyperexcitation of the skeletal muscles. It is due to the downregulation of postsynaptic voltage-gated potassium channels.

As a result, the potassium ions are unable to leave the skeletal muscle and hyperpolarization occurs. This hyperpolarization leads to the hyperexcitation of skeletal muscle and muscle spasms. It is also believed to be an autoimmune disorder of the neuromuscular junction.

Conclusion/Summary

Neuromuscular junction is a microstructure present at the junction of motor neurons and the skeletal muscle fibers. It acts as a bridge connecting the skeletal system and the nervous system.

The neuromuscular junction is a chemical synapse.

The presynaptic terminal is the axonal terminal of motor neuron containing synaptic vesicles.

These vesicles are released into the synaptic cleft when a nerve impulse arrives.

The postjunctional sarcolemma has the synaptic clefts having acetylcholine receptors on their walls.

The acetylcholine molecules released by the presynaptic terminal bind to these receptors and cause the opening of the cation channels.

The sodium ions diffuse through these channels, resulting in depolarization od skeletal muscles. This depolarization initiates the process of muscle contraction.

The acetylcholine is soon metabolized by the acetylcholinesterase, which eliminates all its effects.

The normal mechanism of neuromuscular junction is affected by cholinergic drugs as well as skeletal muscle relaxants.

The cholinergic drugs, which may be direct-acting or indirect-acting, increase the activity of acetylcholine.

The skeletal muscle relaxants are the neuromuscular blockers. The block the neuromuscular junction by inhibiting the depolarization or by causing excessive depolarization.

The important pathologic conditions associated with the neuromuscular junction include:

  • Myasthenia Gravis
  • Lambert-Eaton Syndrome
  • Neuromyotonia

All these are autoimmune conditions. The first two result in muscle weakness while the third one causes hyperextension of skeletal muscles.

References

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