neuromuscular adj : affecting or characteristic of both neural and muscular tissue

English

Adjective

1. Pertaining to the voluntary control of muscles by nerves.

   Mulitple sclerosis is a neuromuscular disease.

A neuromuscular junction (NMJ) is the synapse or junction of the axon terminal of a motoneuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter acetylcholine.

Anatomy

Upon the arrival of an action potential at the axon terminal, voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid into the motor neuron's cytosol. This influx of Ca2+ triggers a biochemical cascade that causes neurotransmitter-containing vesicles to fuse to the motor neuron's cell membrane and release acetylcholine into the synaptic cleft, a process known as exocytosis.

Acetylcholine diffuses across the synaptic cleft and binds to the nicotinic acetylcholine receptors that dot the motor end plate.

The receptors are ligand-gated ion channels, and when bound by acetylcholine, they open, allowing sodium and potassium ions to flow in and out of the muscle's cytosol, respectively.

Because of the differences in electrochemical gradients across the plasma membrane, more sodium moves in than potassium out, producing a local depolarization of the motor end plate known as an end-plate potential (EPP).

This depolarization spreads across the surface of the muscle fiber into transverse tubules, eliciting the release of calcium from the sarcoplasmic reticulum, thus initiating muscle contraction.

The action of acetylcholine is terminated when the enzyme acetylcholinesterase degrades the neurotransmitter and the unhydrolysed neurotransmitter diffuses away.

Development of the neuromuscular junction

The formation of the neuromuscular junction during embryonic development is well understood.

During development, the growing end of motor neuron axons secrete a protein known as agrin.

This protein binds to several receptors on the surface of skeletal muscle.

The receptor which seems to be required for formation of the neuromuscular junction is called the MuSK protein (Muscle specific kinase).

MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the release of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.

Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors (AChR).

In addition to the AChR and MuSK, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the NMJ.

Knockout studies

These findings were demonstrated in part by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in Dok-7 did not form either acetylcholine receptor clusters or neuromuscular synapses.

Many other proteins also comprise the NMJ, and are required to maintain its integrity.

Neuromuscular junction disorders

In diseases such as myasthenia gravis, the EPP fails to effectively activate the muscle fiber due to an autoimmune reaction against acetylcholine receptors, resulting in muscle weakness and fatigue.

Various toxins, such as botulinum toxin prevent the release of acetylcholine, resulting in muscle paralysis. Myasthenia gravis is caused most commonly by auto-antibodies against the acetylcholine receptor.

It has recently been realized that a second category of gravis is due to auto-antibodies against MuSK.

See also

• Synapse
• Skeletal muscle
• Nicotinic acetylcholine receptor
• Neuromuscular blocking drugs

External links

Further reading

• Principles of Neural Science
• From Neuron to Brain
• Myology

References