Neuromuscular junction

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Neuromuscular junction
Neuro Muscular Junction.png
At the neuromuscular junction, the nerve fiber is able to transmit a signal to the muscle fiber by releasing ACh (and other substances), causing muscle contraction
Neuromuscular junction.svg
Schematic view of a neuromuscular junction
Details
Identifiers
Latin synapssis neuromuscularis; junctio neuromuscularis
MeSH D009469
TH H2.00.06.1.02001
FMA 61803
Anatomical terminology
Neural Control (pre-muscle contraction).png

A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. [1]

Contents

It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. [2]

Muscles require innervation to function—and even just to maintain muscle tone, avoiding atrophy. In the neuromuscular system, nerves from the central nervous system and the peripheral nervous system are linked and work together with muscles. [3] Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-gated calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins (synaptotagmins) on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine (ACh), a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors (nAChRs) on the cell membrane of the muscle fiber, also known as the sarcolemma. nAChRs are ionotropic receptors, meaning they serve as ligand-gated ion channels. The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that eventually results in muscle contraction.

Neuromuscular junction diseases can be of genetic and autoimmune origin. Genetic disorders, such as Congenital myasthenic syndrome, can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as myasthenia gravis, occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma.

Structure and function

Quantal transmission

At the neuromuscular junction, presynaptic motor axons terminate 30 nanometers from the cell membrane or sarcolemma of a muscle fiber. The sarcolemma at the junction has invaginations called postjunctional folds, which increase its surface area facing the synaptic cleft. [4] These postjunctional folds form the motor endplate, which is studded with nicotinic acetylcholine receptors (nAChRs) at a density of 10,000 receptors/μm2. [5] The presynaptic axons terminate in bulges called terminal boutons (or presynaptic terminals) that project toward the postjunctional folds of the sarcolemma. In the frog each motor nerve terminal contains about 300,000 vesicles, with an average diameter of 0.05 micrometers. The vesicles contain acetylcholine. Some of these vesicles are gathered into groups of fifty, positioned at active zones close to the nerve membrane. Active zones are about 1 micrometer apart. The 30 nanometer cleft between nerve ending and endplate contains a meshwork of acetylcholinesterase (AChE) at a density of 2,600 enzyme molecules/μm2, held in place by the structural proteins dystrophin and rapsyn. Also present is the receptor tyrosine kinase protein MuSK, a signaling protein involved in the development of the neuromuscular junction, which is also held in place by rapsyn. [4]

About once every second in a resting junction randomly one of the synaptic vesicles fuses with the presynaptic neuron's cell membrane in a process mediated by SNARE proteins. Fusion results in the emptying of the vesicle's contents of 7000–10,000 acetylcholine molecules into the synaptic cleft, a process known as exocytosis. [6] Consequently, exocytosis releases acetylcholine in packets that are called quanta. The acetylcholine quantum diffuses through the acetylcholinesterase meshwork, where the high local transmitter concentration occupies all of the binding sites on the enzyme in its path. The acetylcholine that reaches the endplate activates ~2,000 acetylcholine receptors, opening their ion channels which permits sodium ions to move into the endplate producing a depolarization of ~0.5 mV known as a miniature endplate potential (MEPP). By the time the acetylcholine is released from the receptors the acetylcholinesterase has destroyed its bound ACh, which takes about ~0.16 ms, and hence is available to destroy the ACh released from the receptors.[ citation needed ]

When the motor nerve is stimulated there is a delay of only 0.5 to 0.8 msec between the arrival of the nerve impulse in the motor nerve terminals and the first response of the endplate [7] The arrival of the motor nerve action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels, and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol. This influx of Ca2+ causes several hundred neurotransmitter-containing vesicles to fuse with the presynaptic neuron's cell membrane through SNARE proteins to release their acetylcholine quanta by exocytosis. The endplate depolarization by the released acetylcholine is called an endplate potential (EPP). The EPP is accomplished when ACh binds the nicotinic acetylcholine receptors (nAChR) at the motor end plate, and causes an influx of sodium ions. This influx of sodium ions generates the EPP (depolarization), and triggers an action potential that travels along the sarcolemma and into the muscle fiber via the T-tubules (transverse tubules) by means of voltage-gated sodium channels. [8] The conduction of action potentials along the T-tubules stimulates the opening of voltage-gated Ca2+ channels which are mechanically coupled to Ca2+ release channels in the sarcoplasmic reticulum. [9] The Ca2+ then diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction. The endplate potential is thus responsible for setting up an action potential in the muscle fiber which triggers muscle contraction. The transmission from nerve to muscle is so rapid because each quantum of acetylcholine reaches the endplate in millimolar concentrations, high enough to combine with a receptor with a low affinity, which then swiftly releases the bound transmitter.[ citation needed ]

Acetylcholine receptors

Ion channel linked receptor Ions Ligand (such as acetylcholine) When ligands bind to the receptor, the ion channel portion of the receptor opens, allowing ions to pass across the cell membrane. Ion-Channel Receptor.svg
  1. Ion channel linked receptor
  2. Ions
  3. Ligand (such as acetylcholine)
When ligands bind to the receptor, the ion channel portion of the receptor opens, allowing ions to pass across the cell membrane.

Acetylcholine is a neurotransmitter synthesized from dietary choline and acetyl-CoA (ACoA), and is involved in the stimulation of muscle tissue in vertebrates as well as in some invertebrate animals. In vertebrates, the acetylcholine receptor subtype that is found at the neuromuscular junction of skeletal muscles is the nicotinic acetylcholine receptor (nAChR), which is a ligand-gated ion channel. Each subunit of this receptor has a characteristic "cys-loop", which is composed of a cysteine residue followed by 13 amino acid residues and another cysteine residue. The two cysteine residues form a disulfide linkage which results in the "cys-loop" receptor that is capable of binding acetylcholine and other ligands. These cys-loop receptors are found only in eukaryotes, but prokaryotes possess ACh receptors with similar properties. [5] Not all species use a cholinergic neuromuscular junction; e.g. crayfish and fruit flies have a glutamatergic neuromuscular junction. [4]

AChRs at the skeletal neuromuscular junction form heteropentamers composed of two α, one β, one ɛ, and one δ subunits. [10] When a single ACh ligand binds to one of the α subunits of the ACh receptor it induces a conformational change at the interface with the second AChR α subunit. This conformational change results in the increased affinity of the second α subunit for a second ACh ligand. AChRs, therefore, exhibit a sigmoidal dissociation curve due to this cooperative binding. [5] The presence of the inactive, intermediate receptor structure with a single-bound ligand keeps ACh in the synapse that might otherwise be lost by cholinesterase hydrolysis or diffusion. The persistence of these ACh ligands in the synapse can cause a prolonged post-synaptic response. [11]

Development

The development of the neuromuscular junction requires signaling from both the motor neuron's terminal and the muscle cell's central region. During development, muscle cells produce acetylcholine receptors (AChRs) and express them in the central regions in a process called prepatterning. Agrin, a heparin proteoglycan, and MuSK kinase are thought to help stabilize the accumulation of AChR in the central regions of the myocyte. MuSK is a receptor tyrosine kinase—meaning that it induces cellular signaling by binding phosphate molecules to self regions like tyrosines, and to other targets in the cytoplasm. [12] Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors. [13] ACh release by developing motor neurons produces postsynaptic potentials in the muscle cell that positively reinforces the localization and stabilization of the developing neuromuscular junction. [14]

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. [15]

The development of neuromuscular junctions is mostly studied in model organisms, such as rodents. In addition, in 2015 an all-human neuromuscular junction has been created in vitro using human embryonic stem cells and somatic muscle stem cells. [16] In this model presynaptic motor neurons are activated by optogenetics and in response synaptically connected muscle fibers twitch upon light stimulation.

Research methods

José del Castillo and Bernard Katz used ionophoresis to determine the location and density of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. With this technique, a microelectrode was placed inside the motor endplate of the muscle fiber, and a micropipette filled with acetylcholine (ACh) was placed directly in front of the endplate in the synaptic cleft. A positive voltage was applied to the tip of the micropipette, which caused a burst of positively charged ACh molecules to be released from the pipette. These ligands flowed into the space representing the synaptic cleft and bound to AChRs. The intracellular microelectrode monitored the amplitude of the depolarization of the motor endplate in response to ACh binding to nicotinic (ionotropic) receptors. Katz and del Castillo showed that the amplitude of the depolarization (excitatory postsynaptic potential) depended on the proximity of the micropipette releasing the ACh ions to the endplate. The farther the micropipette was from the motor endplate, the smaller the depolarization was in the muscle fiber. This allowed the researchers to determine that the nicotinic receptors were localized to the motor endplate in high density. [4] [5]

Toxins are also used to determine the location of acetylcholine receptors at the neuromuscular junction. α-Bungarotoxin is a toxin found in the snake species Bungarus multicinctus that acts as an ACh antagonist and binds to AChRs irreversibly. By coupling assayable enzymes such as horseradish peroxidase (HRP) or fluorescent proteins such as green fluorescent protein (GFP) to the α-bungarotoxin, AChRs can be visualized and quantified. [4]

Toxins that affect the neuromuscular junction

Nerve gases

Nerve gases bind to and phosphorylate AChE, effectively deactivating them. The accumulation of ACh within the synaptic cleft causes muscle cells to be perpetually contracted, leading to severe complications such as paralysis and death within minutes of exposure.

Botulinum toxin injected in human face Dr Braun Performs a Botox Injection (4035273577).jpg
Botulinum toxin injected in human face

Botulinum toxin

Botulinum toxin (also known as botulinum neurotoxin, and commercially sold under the trade name Botox) inhibits the release of acetylcholine at the neuromuscular junction by interfering with SNARE proteins. [4] This toxin crosses into the nerve terminal through the process of endocytosis and subsequently cleaves SNARE proteins, preventing the ACh vesicles from fusing with the intracellular membrane. This induces a transient flaccid paralysis and chemical denervation localized to the striated muscle that it has affected. The inhibition of ACh release does not set in until approximately two weeks after the injection is made. Three months after the inhibition occurs, neuronal activity begins to regain partial function, and six months after, complete neuronal function is regained. [17]

Tetanus toxin

Tetanus toxin, also known as tetanospasmin is a potent neurotoxin produced by Clostridium tetani and causes the disease state, tetanus. The LD50 of this toxin has been measured to be approximately 1 ng/kg, making it second only to botulinum toxin D as the deadliest toxin in the world. It functions very similarly to botulinum neurotoxin by attaching and endocytosing into the presynaptic nerve terminal and interfering with SNARE proteins. It differs from botulinum neurotoxin in a few ways, most apparently in its end state, wherein tetanospasmin causes spastic paralysis as opposed to the flaccid paralysis demonstrated with botulinum neurotoxin.

Latrotoxin

Latrotoxin (α-Latrotoxin) found in venom of widow spiders also affects the neuromuscular junction by causing the release of acetylcholine from the presynaptic cell. Mechanisms of action include binding to receptors on the presynaptic cell activating the IP3/DAG pathway and release of calcium from intracellular stores and pore formation resulting in influx of calcium ions directly. Either mechanism causes increased calcium in presynaptic cell, which then leads to release of synaptic vesicles of acetylcholine. Latrotoxin causes pain, muscle contraction and if untreated potentially paralysis and death.

Snake venom

Snake venoms act as toxins at the neuromuscular junction and can induce weakness and paralysis. Venoms can act as both presynaptic and postsynaptic neurotoxins. [18]

Presynaptic neurotoxins, commonly known as β-neurotoxins, affect the presynaptic regions of the neuromuscular junction. The majority of these neurotoxins act by inhibiting the release of neurotransmitters, such as acetylcholine, into the synapse between neurons. However, some of these toxins have also been known to enhance neurotransmitter release. Those that inhibit neurotransmitter release create a neuromuscular blockade that prevents signaling molecules from reaching their postsynaptic target receptors. In doing so, the victim of these snake bite suffer from profound weakness. Such neurotoxins do not respond well to anti-venoms. After one hour of inoculation of these toxins, including notexin and taipoxin, many of the affected nerve terminals show signs of irreversible physical damage, leaving them devoid of any synaptic vesicles. [18]

Postsynaptic neurotoxins, otherwise known as α-neurotoxins, act oppositely to the presynaptic neurotoxins by binding to the postsynaptic acetylcholine receptors. This prevents interaction between the acetylcholine released by the presynaptic terminal and the receptors on the postsynaptic cell. In effect, the opening of sodium channels associated with these acetylcholine receptors is prohibited, resulting in a neuromuscular blockade, similar to the effects seen due to presynaptic neurotoxins. This causes paralysis in the muscles involved in the affected junctions. Unlike presynaptic neurotoxins, postsynaptic toxins are more easily affected by anti-venoms, which accelerate the dissociation of the toxin from the receptors, ultimately causing a reversal of paralysis. These neurotoxins experimentally and qualitatively aid in the study of acetylcholine receptor density and turnover, as well as in studies observing the direction of antibodies toward the affected acetylcholine receptors in patients diagnosed with myasthenia gravis. [18]

Diseases

Any disorder that compromises the synaptic transmission between a motor neuron and a muscle cell is categorized under the umbrella term of neuromuscular diseases. These disorders can be inherited or acquired and can vary in their severity and mortality. In general, most of these disorders tend to be caused by mutations or autoimmune disorders. Autoimmune disorders, in the case of neuromuscular diseases, tend to be humoral mediated, B cell mediated, and result in an antibody improperly created against a motor neuron or muscle fiber protein that interferes with synaptic transmission or signaling.

Autoimmune

Myasthenia gravis

Myasthenia gravis is an autoimmune disorder where the body makes antibodies against either the acetylcholine receptor (AchR) (in 80% of cases), or against postsynaptic muscle-specific kinase (MuSK) (0–10% of cases). In seronegative myasthenia gravis low density lipoprotein receptor-related protein 4 is targeted by IgG1, which acts as a competitive inhibitor of its ligand, preventing the ligand from binding its receptor. It is not known if seronegative myasthenia gravis will respond to standard therapies. [19]

Neonatal MG

Neonatal MG is an autoimmune disorder that affects 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis (MG). MG can be transferred from the mother to the fetus by the movement of AChR antibodies through the placenta. Signs of this disease at birth include weakness, which responds to anticholinesterase medications, as well as fetal akinesia, or the lack of fetal movement. This form of the disease is transient, lasting for about three months. However, in some cases, neonatal MG can lead to other health effects, such as arthrogryposis and even fetal death. These conditions are thought to be initiated when maternal AChR antibodies are directed to the fetal AChR and can last until the 33rd week of gestation, when the γ subunit of AChR is replaced by the ε subunit. [20] [21]

Lambert-Eaton myasthenic syndrome

Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder that affects the presynaptic portion of the neuromuscular junction. This rare disease can be marked by a unique triad of symptoms: proximal muscle weakness, autonomic dysfunction, and areflexia. [22] Proximal muscle weakness is a product of pathogenic autoantibodies directed against P/Q-type voltage-gated calcium channels, which in turn leads to a reduction of acetylcholine release from motor nerve terminals on the presynaptic cell. Examples of autonomic dysfunction caused by LEMS include erectile dysfunction in men, constipation, and, most commonly, dry mouth. Less common dysfunctions include dry eyes and altered perspiration. Areflexia is a condition in which tendon reflexes are reduced and it may subside temporarily after a period of exercise. [23]

50–60% of the patients that are diagnosed with LEMS also have present an associated tumor, which is typically small-cell lung carcinoma (SCLC). This type of tumor also expresses voltage-gated calcium channels. [23] Oftentimes, LEMS also occurs alongside myasthenia gravis. [22]

Treatment for LEMS consists of using 3,4-diaminopyridine as a first measure, which serves to increase the compound muscle action potential as well as muscle strength by lengthening the time that voltage-gated calcium channels remain open after blocking voltage-gated potassium channels. In the US, treatment with 3,4-diaminopyridine for eligible LEMS patients is available at no cost under an expanded access program. [24] [25] Further treatment includes the use of prednisone and azathioprine in the event that 3,4-diaminopyridine does not aid in treatment. [23]

Neuromyotonia

Neuromyotonia (NMT), otherwise known as Isaac's syndrome, is unlike many other diseases present at the neuromuscular junction. Rather than causing muscle weakness, NMT leads to the hyperexcitation of motor nerves. NMT causes this hyperexcitation by producing longer depolarizations by down-regulating voltage-gated potassium channels, which causes greater neurotransmitter release and repetitive firing. This increase in rate of firing leads to more active transmission and as a result, greater muscular activity in the affected individual. NMT is also believed to be of autoimmune origin due to its associations with autoimmune symptoms in the individual affected. [20]

Genetic

Congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are very similar to both MG and LEMS in their functions, but the primary difference between CMS and those diseases is that CMS is of genetic origins. Specifically, these syndromes are diseases incurred due to mutations, typically recessive, in 1 of at least 10 genes that affect presynaptic, synaptic, and postsynaptic proteins in the neuromuscular junction. Such mutations usually arise in the ε-subunit of AChR, [20] thereby affecting the kinetics and expression of the receptor itself. Single nucleotide substitutions or deletions may cause loss of function in the subunit. Other mutations, such as those affecting acetylcholinesterase and acetyltransferase, can also cause the expression of CMS, with the latter being associated specifically with episodic apnea. [26] These syndromes can present themselves at different times within the life of an individual. They may arise during the fetal phase, causing fetal akinesia, or the perinatal period, during which certain conditions, such as arthrogryposis, ptosis, hypotonia, ophthalmoplegia, and feeding or breathing difficulties, may be observed. They could also activate during adolescence or adult years, causing the individual to develop slow-channel syndrome. [20]

Treatment for particular subtypes of CMS (postsynaptic fast-channel CMS) [27] [28] is similar to treatment for other neuromuscular disorders. 3,4-Diaminopyridine, the first-line treatment for LEMS, is under development as an orphan drug for CMS [29] in the US, and available to eligible patients under an expanded access program at no cost. [24] [25]

See also

Related Research Articles

<span class="mw-page-title-main">Lambert–Eaton myasthenic syndrome</span> Medical condition

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy.

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Acetylcholine receptor</span> Integral membrane protein

An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

<span class="mw-page-title-main">Excitatory postsynaptic potential</span> Process causing temporary increase in postsynaptic potential

In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the flow of positively charged ions into the postsynaptic cell, is a result of opening ligand-gated ion channels. These are the opposite of inhibitory postsynaptic potentials (IPSPs), which usually result from the flow of negative ions into the cell or positive ions out of the cell. EPSPs can also result from a decrease in outgoing positive charges, while IPSPs are sometimes caused by an increase in positive charge outflow. The flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC).

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Edrophonium</span>

Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is sold under the trade names Tensilon and Enlon.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">Synaptic vesicle</span> Neurotransmitters that are released at the synapse

In 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. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

<span class="mw-page-title-main">End-plate potential</span> Voltages associated with muscle fibre

End plate potentials (EPPs) are the voltages which cause depolarization 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. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

<span class="mw-page-title-main">MuSK protein</span> Mammalian protein found in Homo sapiens

MuSK is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscular junction formation.

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 (PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.

α-Bungarotoxin Chemical compound

α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.

Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference being that CMS is not an autoimmune disorder. There are only 600 known family cases of this disorder and it is estimated that its overall frequency in the human population is 1 in 200,000.

<span class="mw-page-title-main">RAPSN</span> Protein-coding gene in the species Homo sapiens

43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.

<span class="mw-page-title-main">CHRNE</span> Protein-coding gene

Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

Repetitive nerve stimulation is a variant of the nerve conduction study where electrical stimulation is delivered to a motor nerve repeatedly several times per second. By observing the change in the muscle electrical response (CMAP) after several stimulations, a physician can assess for the presence of a neuromuscular junction disease, and differentiate between presynaptic and postsynaptic conditions. The test was first described by German neurologist Friedrich Jolly in 1895, and is also known as Jolly's test.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Tetanic fade refers to the diminishing muscle twitch response from an evoked potential stimulation of muscle under the effect of either a non-depolarizing neuromuscular blocking agent, or a muscle that is under a phase 2 depolarizing neuromuscular blocking agent.

References

  1. ↑ Levitan I, Kaczmarek L (August 19, 2015). "Intercellular communication". The Neuron: Cell and Molecular Biology (4th ed.). New York, NY: Oxford University Press. pp. 153–328. ISBN   978-0199773893.
  2. ↑ Jimsheleishvili S, Marwaha K, Sherman AL (2024), "Physiology, Neuromuscular Transmission", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   31082177 , retrieved 2024-08-26
  3. ↑ Rygiel KA, Picard M, Turnbull DM (August 2016). "The ageing neuromuscular system and sarcopenia: a mitochondrial perspective". The Journal of Physiology. 594 (16): 4499–4512. doi:10.1113/JP271212. PMC   4983621 . PMID   26921061.
  4. 1 2 3 4 5 6 Nicholls, John G., A. Robert Martin, Paul A. Fuchs, David A. Brown, Matthew E. Diamond, David A. Weisblat (2012). From Neuron to Brain (5th ed.). Sunderland: Sinauer Associates.
  5. 1 2 3 4 Sine SM (July 2012). "End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease". Physiological Reviews. 92 (3): 1189–1234. doi:10.1152/physrev.00015.2011. PMC   3489064 . PMID   22811427.
  6. ↑ Van der Kloot W, Molgó J (October 1994). "Quantal acetylcholine release at the vertebrate neuromuscular junction". Physiological Reviews. 74 (4): 899–991. doi:10.1152/physrev.1994.74.4.899. PMID   7938228.
  7. ↑ Katz B (1966). Nerve, muscle, and synapse. New York: McGraw-Hill. p. 114.
  8. ↑ McKinley M, O'Loughlin V, Pennefather-O'Brien E, Harris R (2015). Human Anatomy. New York: McGraw-Hill Education. p. 300. ISBN   978-0-07-352573-0.
  9. ↑ Fox S (2016). Human Physiology. New York: McGraw-Hill Education. p. 372. ISBN   978-0-07-783637-5.
  10. ↑ miller's anaesthesia, 7th edition.
  11. ↑ Scuka M, Mozrzymas JW (1992). "Postsynaptic potentiation and desensitization at the vertebrate end-plate receptors". Progress in Neurobiology. 38 (1): 19–33. doi:10.1016/0301-0082(92)90033-B. PMID   1736323. S2CID   38497982.
  12. ↑ Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, et al. (September 1995). "Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury". Neuron. 15 (3): 573–584. doi: 10.1016/0896-6273(95)90146-9 . PMID   7546737. S2CID   17575761.
  13. ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, et al. (May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513–523. doi: 10.1016/S0092-8674(00)81252-0 . PMID   8653787. S2CID   14930468.
  14. ↑ Witzemann V (November 2006). "Development of the neuromuscular junction". Cell and Tissue Research. 326 (2): 263–271. doi:10.1007/s00441-006-0237-x. hdl: 11858/00-001M-0000-002B-BE74-A . PMID   16819627. S2CID   30829665.
  15. ↑ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, et al. (June 2006). "The muscle protein Dok-7 is essential for neuromuscular synaptogenesis". Science. 312 (5781): 1802–1805. Bibcode:2006Sci...312.1802O. doi:10.1126/science.1127142. PMID   16794080. S2CID   45730054.
  16. ↑ Steinbeck JA, Jaiswal MK, Calder EL, Kishinevsky S, Weishaupt A, Toyka KV, et al. (January 2016). "Functional Connectivity under Optogenetic Control Allows Modeling of Human Neuromuscular Disease". Cell Stem Cell. 18 (1): 134–143. doi:10.1016/j.stem.2015.10.002. PMC   4707991 . PMID   26549107.
  17. ↑ Papapetropoulos S, Singer C (April 2007). "Botulinum toxin in movement disorders". Seminars in Neurology. 27 (2): 183–194. doi:10.1055/s-2007-971171. PMID   17390263.
  18. 1 2 3 Lewis RL, Gutmann L (June 2004). "Snake venoms and the neuromuscular junction". Seminars in Neurology. 24 (2): 175–179. doi:10.1055/s-2004-830904. PMID   15257514.
  19. ↑ Finsterer J, Papić L, Auer-Grumbach M (October 2011). "Motor neuron, nerve, and neuromuscular junction disease". Current Opinion in Neurology. 24 (5): 469–474. doi:10.1097/WCO.0b013e32834a9448. PMID   21825986.
  20. 1 2 3 4 Newsom-Davis J (July 2007). "The emerging diversity of neuromuscular junction disorders". Acta Myologica. 26 (1): 5–10. PMC   2949330 . PMID   17915563.
  21. ↑ Bardhan M, Dogra H, Samanta D (2021). "Neonatal Myasthenia Gravis". StatPearls. StatPearls. PMID   32644361.
  22. 1 2 Luigetti M, Modoni A, Lo Monaco M (April 2013). "Low rate repetitive nerve stimulation in Lambert-Eaton myasthenic syndrome: peculiar characteristics of decremental pattern from a single-centre experience". Clinical Neurophysiology. 124 (4): 825–826. doi:10.1016/j.clinph.2012.08.026. PMID   23036181. S2CID   11396376.
  23. 1 2 3 Titulaer MJ, Lang B, Verschuuren JJ (December 2011). "Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies". The Lancet. Neurology. 10 (12): 1098–1107. doi:10.1016/S1474-4422(11)70245-9. PMID   22094130. S2CID   27421424.
  24. 1 2 "LEMS: Firdapse Study Shows Encouraging Results". Muscular Dystrophy Association Press Release. Archived from the original on 10 November 2015.
  25. 1 2 Radke J (30 October 2014). "Catalyst Using the Expanded Access Program to Conduct Phase IV Study with LEMS Patients". Rare Disease Report. Archived from the original on 2015-07-25.
  26. ↑ Harper CM (March 2004). "Congenital myasthenic syndromes". Seminars in Neurology. 24 (1): 111–123. doi:10.1055/s-2004-829592. PMID   15229798.
  27. ↑ Engel AG, Shen XM, Selcen D, Sine SM (April 2015). "Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment". The Lancet. Neurology. 14 (4): 420–434. doi:10.1016/S1474-4422(14)70201-7. PMC   4520251 . PMID   25792100.
  28. ↑ Engel AG, Shen XM, Selcen D, Sine S (December 2012). "New horizons for congenital myasthenic syndromes". Annals of the New York Academy of Sciences. 1275 (1): 54–62. Bibcode:2012NYASA1275...54E. doi:10.1111/j.1749-6632.2012.06803.x. PMC   3546605 . PMID   23278578.
  29. ↑ "Amifampridine phosphate for the treatment of congenital myasthenic syndromes". FDA orphan drug designation. U.S. Food and Drug Administration. Archived from the original on 26 July 2015.

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