Electron micrograph showing a cross section through the neuromuscular junction. T is the axon terminal, M is the muscle fiber. The arrow shows junctional folds with basal lamina. Postsynaptic densities are visible on the tips between the folds. Scale is 0.3 µm. Source: NIMH

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.

[edit] Anatomy

Global view of a neuromuscular junction:
1. Axon
2. Motor end-plate
3. Muscle fiber
4. Myofibril

Motor neuron (efferent) axons originating in the spinal cord enter muscle fibers, where they split into many unmyelinated branches. These terminal fibers run along the myocytes to end at the neuromuscular junction, which occupies a depression in the sarcolemma. Each motor neuron can innervate from one to over 25,000 ^[1] muscle fibers, but muscle fiber receives inputs from only one motor neuron.

In the terminal bouton of the motor nerve, structures known as presynaptic active zones accumulate synaptic vesicles filled with the neurotransmitter acetylcholine.

On the muscle side of the junction, the muscle fiber is folded into grooves called prejunctional folds that mirror the postsynaptic active zones, the spaces between the folds contain the enzyme acetylcholinesterase.

The muscle surface is covered by the synaptic basal lamina. Postjunctional folds are characteristic of skeletal muscle, particularly in fast muscle fibers.

[edit] Mechanism of action

Detailed view of a neuromuscular junction:
1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion

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.

Acetylcholine is a neurotransmitter synthesized in the human body from dietary choline and acetyl coenzyme A. One of the first neurotransmitters discovered, the substance was originally referred to as "vagusstoff" because it was found to be released by the stimulation of the vagus nerve. Later, it was established that acetylcholine is, in fact, important in the stimulation of all muscle tissue and that its action may be either excitatory or inhibitory, depending on a number of factors. Within the body, the synaptic action of acetylcholine usually quickly comes to a halt, the neurotransmitter naturally breaking down soon after its release. However, some nerve gases are designed to thwart this breakdown, causing prolonged stimulation of the receptor cells and resulting in severe muscle spasms

[edit] 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).^[2]

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.^[3]

Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors (AChR).^[4]

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.

[edit] 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.^[5]

Many other proteins also comprise the NMJ, and are required to maintain its integrity.^[6]

[edit] See also

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

[edit] External links

• Histology at BU 21501lca

[edit] Further reading

• Kandel, ER; Schwartz JH, Jessell TM. (2000). Principles of Neural Science (4th ed. ed.). New York: McGraw-Hill. ISBN 0-8385-7701-6. 
• Nicholls, J.G.; A.R. Martin, B.G. Wallace and P.A. Fuchs (2001). From Neuron to Brain (4th ed. ed.). Sunderland, MA.: Sinauer Associates. ISBN 0878934391. 
• Engel, A.G. (2004). Myology (3rd ed. ed.). New York: McGraw Hill Professional. ISBN 0-07-137180-X. 

[edit] References

1. ^ Dale Purves (Editor), George J. Augustine (Editor), David Fitzpatrick (Editor), William C. Hall (Editor), Anthony-Samuel Lamantia (Editor), James O. McNamara (Editor), S. Mark Williams (Editor) (2005). Neurosciences (3 ed.). pp.377. ISBN 978-0878937257. 
2. ^ DeChiara T, Bowen D, Valenzuela D, Simmons M, Poueymirou W, Thomas S, Kinetz E, Compton D, Rojas E, Park J, Smith C, DiStefano P, Glass D, Burden S, Yancopoulos G (1996). "The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo". Cell 85 (4): 501–12. doi:10.1016/S0092-8674(00)81251-9. PMID 8653786. 
3. ^ Valenzuela D, Stitt T, DiStefano P, Rojas E, Mattsson K, Compton D, Nuñez L, Park J, Stark J, Gies D (1995). "Receptor tyrosine sinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury". Neuron 15 (3): 573–84. doi:10.1016/0896-6273(95)90146-9. PMID 7546737. 
4. ^ Glass D, Bowen D, Stitt T, Radziejewski C, Bruno J, Ryan T, Gies D, Shah S, Mattsson K, Burden S, DiStefano P, Valenzuela D, DeChiara T, Yancopoulos G (1996). "Agrin acts via a MuSK receptor complex". Cell 85 (4): 513–23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. 
5. ^ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y (2006). "The muscle protein Dok-7 is essential for neuromuscular synaptogenesis". Science 312 (5781): 1802–5. doi:10.1126/science.1127142. PMID 16794080.  link
6. ^ Strochlic L, Cartaud A, Cartaud J (2005). "The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions". Bioessays 27 (11): 1129–35. doi:10.1002/bies.20305. PMID 16237673.