A
neuromuscular junction (
NMJ) is the synapse or junction of the
axonAn axon or nerve fiber is a long, slender projectionof a nerve cell, or neuron, that conducts electrical impulsesaway from the neuron's cell body or soma....
terminal of a motoneuron with the
motor end plate, the highly-excitable region of
muscle fiberMuscle is the contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
plasma membrane responsible for initiation of
action potentialAn action potential is a transient alteration of the transmembrane voltage across an excitable membrane generated by the activity of voltage-gated ion channels embedded in the membrane. Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and...
s across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
.
Mechanism of action
Upon the arrival of an
action potentialAn action potential is a transient alteration of the transmembrane voltage across an excitable membrane generated by the activity of voltage-gated ion channels embedded in the membrane. Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and...
at the axon terminal,
voltage-dependent calcium channelVoltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+. At physiologic or resting membrane potential, VDCCs are normally closed...
s open and Ca
2+ ions flow from the
extracellular fluidExtracellular fluid usually denotes all body fluid outside of cells. The remainder is called intracellular fluid.In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma...
into the motor neuron's
cytosolThe cytosol or intracellular fluid is the liquid found inside cells. In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion...
. This influx of Ca
2+ triggers a biochemical cascade that causes
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
-containing
vesiclesIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
to fuse to the motor neuron's
cell membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
and release acetylcholine into the synaptic cleft, a process known as
exocytosisExocytosis is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
.
Acetylcholine diffuses across the synaptic cleft and binds to the
nicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons...
s that dot the motor end plate.
The receptors are
ligand-gated ion channelLigand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
s, and when bound by acetylcholine, they open, allowing sodium to flow in and potassium ions to flow out the muscle's cytosol.
Because of the differences in
electrochemicalElectrochemistry is a branch of chemistry that studies chemical reactions which take place in a solution at the interface of an electron conductor and an ionic conductor , and which involve electron transfer between the electrode and the electrolyte or species in solution.If a chemical reaction is...
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 potentialEnd plate potentials are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance...
(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
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
acetylcholinesteraseAcetylcholinesterase, also known as AChE, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic synapses in the central nervous system, where its activity serves to terminate synaptic...
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
Development of the neuromuscular junction
The formation of the neuromuscular junction during embryonic development is well understood.
During development, the
growing endA growth cone is a dynamic, actin-supported extension of a developing axon seeking its synaptic target. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope...
of
motor neuronIn vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
axons secrete a
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
known as
agrinAgrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRIN...
.
This protein binds to several
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
s on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is called "LRP4" and not the formerly considered
MuSK proteinMuSK is a receptor tyrosine kinase required for the formation of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.-MuSK is required for formation of the Neuromuscular Junction:...
(Muscle specific kinase).
MuSK is a receptor
tyrosine kinaseA tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases...
- meaning that it induces cellular signaling by causing the release of
phosphateA phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
molecules to particular
tyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
s on itself, and on proteins which bind the
cytoplasmThe cytoplasm is the part of a cell that is enclosed within the cell membrane. In eukaryotic cells, the cytoplasm contains organelles, such as mitochondria, which are filled with liquid that is kept separate from the rest of the cytoplasm by biological membranes. The contents of the cell nucleus...
ic
domainA protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
of the receptor.
Upon activation by its ligand agrin, MuSK signals via two proteins called "
Dok-7Dok-7 is a cytoplasmic protein containing a Plekstrin Homology domain and a PTB domain which serves an essential signaling step in the formation of the Neuromuscular Junction .-Dok-7 is required for formation of the Neuromuscular Junction:...
" and "
rapsynRapsyn is a 43 kDa cytoplasmic membrane-associated protein that tightly associates with the intracellular domain of acetylcholine receptors and is detected at neuromuscular junctions as soon as AChRs cluster. When rapsyn is knocked out in mice, they don't undergo AChR clustering....
", to induce "clustering" of
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
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-7Dok-7 is a cytoplasmic protein containing a Plekstrin Homology domain and a PTB domain which serves an essential signaling step in the formation of the Neuromuscular Junction .-Dok-7 is required for formation of the Neuromuscular Junction:...
did not form either acetylcholine receptor clusters or neuromuscular synapses.
Many other proteins also comprise the NMJ, and are required to maintain its integrity.
See also
- Synapse
- Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system. It is one of three major muscle types, the others being cardiac and smooth muscle. As its name suggests, skeletal muscle is linked to bone by bundles of collagen fibers known as...
- Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons...
- Neuroeffector junction
A neuroeffector junction is the site where a motor neuron releases a neurotransmitter to affect a target cell. This junction functions like a synapse. Somatic efferent motor neurons innervate skeletal muscle, and are always excitatory. Visceral efferent neurons innervate smooth muscle, cardiac...
- Neuromuscular blocking drugs
- Neuromuscular junction disease
Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.-Autoimmune:...