Neuromuscular junction
Encyclopedia
A neuromuscular junction (NMJ) is the synapse
or junction of the axon
terminal of a motor neuron
with the motor end plate, the highly-excitable region of muscle fiber
plasma membrane responsible for initiation of action potential
s across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter
acetylcholine
.
of skeletal muscle.
Acetylcholine is a neurotransmitter synthesized in the human body from dietary choline
and acetyl-CoA
(ACoA). 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.
During development, the growing end
of motor neuron
axons secrete a protein
known as agrin
.
This protein binds to several receptor
s on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is 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 tyrosine
s on itself, and on proteins which bind the cytoplasm
ic 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.
did not form either acetylcholine receptor clusters or neuromuscular synapses.
Many other proteins also comprise the NMJ, and are required to maintain its integrity.
s or be intentionally induced with neuromuscular blocking drugs. It can also be a side effect of other drugs that are generally not classified as neuromuscular blocking drugs, such as some anesthetic drugs.
The degree of neuromuscular block may be estimated by Bromage score, which originally had four grades designate with the Roman numerals I until IV, but later complemented by Breen et al with an inverse grading with Hindu-Arabic numerals:
In unconscious patients, such as during anesthesia
, neural block can be assessed by a "train-of-four" by stimulating musclesfrom surface electrodes.
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
or junction of the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
terminal of a motor neuron
Motor neuron
In 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...
with the motor end plate, the highly-excitable region of muscle fiber
Muscle
Muscle is a contractile tissue of animals 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 potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
.
Mechanism of action
The neuromuscular junction is the location where the neuron activates muscle to contract. This is a step in the excitation-contraction couplingExcitation-contraction coupling
Excitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical...
of skeletal muscle.
- Upon the arrival of an action potentialAction potentialIn physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
at the presynaptic neuron terminal, voltage-dependent calcium channelVoltage-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+...
s open and Ca2+ ions flow from the extracellular fluidExtracellular 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 presynaptic neuron's cytosolCytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. - This influx of Ca2+ causes neurotransmitterNeurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
-containing vesiclesSynaptic vesicleIn 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 dock and fuse to the presynaptic neuron's cell membraneCell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
through SNARESNARE (protein)SNARE proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells....
proteins. - Fusion of the vesicular membrane with the presynaptic cell membrane results in the emptying of the vesicle's contents (acetylcholine) into the synaptic cleftSynapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, a process known as exocytosisExocytosisExocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
. - Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptorNicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s bound to the motor end plate. - These receptors are ligand-gated ion channelLigand-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 they bind acetylcholine, they open, allowing sodium ions to flow in and potassium ions to flow out of the muscle's cytosol. - Because of the differences in electrochemicalElectrochemistryElectrochemistry 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 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 and continues the excitation-contraction couplingExcitation-contraction couplingExcitation-contraction coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response . This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical...
to contract the muscle. - The action of acetylcholine is terminated when the enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
acetylcholinesteraseAcetylcholinesterase"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
degrades part of the neurotransmitter (producing cholineCholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
and an acetateAcetateAn acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
group) and the rest of it diffuses away. - The choline produced by the action of acetylcholinesterase is recycled — it is transported, through reuptakeReuptakeReuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
, back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.
Acetylcholine is a neurotransmitter synthesized in the human body from dietary choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
and acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
(ACoA). 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 complex series of steps leading to the formation of the neuromuscular junction during embryonic development are only partially understood.During development, the growing end
Growth cone
A 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 neuron
Motor neuron
In 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 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
known as agrin
Agrin
Agrin 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 AGRN...
.
This protein binds to several receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is the MuSK protein
MuSK protein
MuSK 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 kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
- meaning that it induces cellular signaling by causing the release of phosphate
Phosphate
A 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 tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s on itself, and on proteins which bind the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic domain
Protein domain
A 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-7
Dok-7
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
" and "rapsyn", to induce "clustering" of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
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
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology and phosphotyrosine-binding domains that are critical for Dok-7 function...
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 block
A block or decrease in the transmission across the neuromuscular junction can cause a complete or relative loss of muscle function. It can result from neuromuscular junction diseaseNeuromuscular junction disease
Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.-Autoimmune:...
s or be intentionally induced with neuromuscular blocking drugs. It can also be a side effect of other drugs that are generally not classified as neuromuscular blocking drugs, such as some anesthetic drugs.
The degree of neuromuscular block may be estimated by Bromage score, which originally had four grades designate with the Roman numerals I until IV, but later complemented by Breen et al with an inverse grading with Hindu-Arabic numerals:
| Bromage score | |||
|---|---|---|---|
| Grade | Criteria | Approximate degree of block |
|
| IV | 1 | Complete block, inability to move feet or knees | 100% |
| III | 2 | Almost complete block, ability to move feet only, with inability to flex knees | 66% |
| II | 3 | Partial block, ability to flex knees | 33% |
| 4 | Detectable weakness of hip flexion while supine, ability of full flexion of knees | ||
| 5 | No detectable weakness of hip flexion while supine | ||
| I | 6 | Free movement of legs and feet, ability to perform partial knee bend | 0% |
In unconscious patients, such as during anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
, neural block can be assessed by a "train-of-four" by stimulating musclesfrom surface electrodes.
See also
- SynapseSynapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
- Skeletal muscleSkeletal muscleSkeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
- Nicotinic acetylcholine receptorNicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
- Neuroeffector junctionNeuroeffector junctionA 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...