- Motor End Plate
- Synaptic Cleft
- Sub-Neural Clefts
- Axon Terminal
- Degradation of Acetylcholine
- End plate potential(EPP)
- Toxins affecting the Neuromuscular Junction
- Auto immune disorders
- Genetic Disorders
- Frequently Asked Questions
- What are the 3 parts of a neuromuscular junction?
- What is the function of the neuromuscular junction?
- What type of muscle tissue has neuromuscular junction?
- What type of neurotransmitter is released at the neuromuscular junction?
The neuromuscular junctions play the important role of transferring action potentials to the skeletal muscle fibers. Fibers of the skeletal muscles are innervated by large, myelinated nerve fibers that originate in the large motor neurons in the anterior horn of the spinal cord. All of these fibers branch out to innervate anywhere from between a few to several hundred muscle fibers.
The neuromuscular junctions act as the point of interaction between the neurons and the muscle fibers. These neuromuscular junctions allow the action potentials to travel from the neurons to the muscle fibers where they travel towards both ends of the fibers. In about 98 percent of the muscle fibers there is only one neuromuscular junction supplying them.
Thus, it is important to understand the normal anatomy and physiology, the different toxins, pathologies that affect them and the drugs that act on the neuromuscular junction in order for us to fully understand the overall functioning of the skeletal muscles.
In order for it to develop, the neuro muscular junction requires signals from both the nerve fiber terminals and the central region of the skeletal muscle fibers. Through a process called pre-patterning, the skeletal muscle fibers accumulate their acetylcholine receptors (Ach-R) in their central regions. This process of accumulation is facilitated by the presence of “MuSK kinase” and a Heparin proteoglycan called “Agrin”. MuSK being a receptor Tyrosine kinase induces signals by phosphorylating Tyrosine in self regions and in other cytoplasmic target regions. Upon binding to its ligand, the activated MuSK releases “Rapsyn” and “Dok7”. These two proteins induce the huddling of the ACh-R. Further, the developing nerve fibers release ACh into the synaptic cleft which induces potentials in the post synaptic membrane. This further stabilizes the neuromuscular junction and contributes to its development. Although most of these findings were observed in research conducted on rodents and other organisms, in 2015 scientists were able to create an all human neuro muscular junction in Vitro.
This section describes the anatomy of the neuromuscular junction in order make it easier to understand its overall functioning. The complex structure of the neuromuscular junction allows it to link the nervous system to the skeletal muscles allowing them to work together.
Motor End Plate
Overall, the structure of the neuro muscular junction can be divided into the terminal button, the presynaptic membrane, the synaptic cleft, and the post synaptic membrane. The myelinated nerve fibers upon reaching their terminal branch outwards to form a system of branching nerve terminals. These branching nerve terminals invaginate into the muscle fibers however they lie entirely separated and outside of plasma membrane of the muscle fibers. This invagination of the nerve terminal into the muscle fibers is known as the synaptic trough or the synaptic gutter. This entire structure is known as the motor end plate. This motor end plate is completely surrounded by one or more Schwan cells that insulate it from the fluids that surround it.
On electro micrographic examination, a clear gap is visible between the neuronal terminal membrane and the muscle fiber membrane, known as the synaptic cleft. The synaptic cleft is 20 to 30 nanometers wide and is occupied by thin spongy layers of the reticular fibers. These reticular fibers are actually basal lamina, and they allow the diffusion of extra cellular fluid.
In order to increase neurotransmission, the muscular membranes display numerous small folds known as Sub-neural clefts these greatly increase the surface are for the synaptic transmission to occur.
On close examination the axon terminals are found to contain numerous mitochondria. These supply the energy for the synthesis of acetylcholine, the excitatory transmitter. Upon their synthesis in the terminal axonal cytoplasm the acetylcholine molecules are immediately packed in small synaptic vesicles and shifted towards the presynaptic membrane. on average three hundred thousand of such vesicles are found in nerve terminals. ACh also directly affect vasculature by binding to muscarinic receptors on the endothelium which causes the release of nitric oxide causing vasodilation Further the acetylcholinesterase enzymes are found in large quantities in the basement membranes, cause the degradation of acetylcholine in the synaptic cleft.
Acetylcholine (ACh) is the neurotransmitter used in the neuro muscular junction. Chemically, it is an ester bond between acetic acid and choline. Parts of the body making use of or being affected by ACh are known as Cholinergic. The major sites where ACh is used are the neuro muscular junctions where it stimulates muscle fibers and the Autonomic system where it acts in both the sympathetic and the parasympathetic ganglia. It also acts on the parasympathetic target organ receptors as well as in the stimulation of the adrenal gland. There are two types of ACh receptors muscarinic receptors that occur in the receptors in the target organ receptors in parasympathetic system and the Nicotinic receptors that occur in both the sympathetic and parasympathetic ganglia and in the target organ receptors in the adrenal gland and the somatic stimulation i.e. the Neuromuscular junction. Further according to pharmacologic evidence, ACh also plays a key role in the formation of memory thus a disruption in its transmission can have adverse implications.
Acetylcholine is formed when a molecule choline is attached to acetyl coenzyme A under the presence of the Choline acyl-transferase enzyme. In relevance to the topic, Choline is absorbed in the axonal nerve terminals from the surroundings via high affinity choline transporter, this can be blocked by Hemicholinium. Furthermore, ACh can be broken down by the enzyme Acetylcholinesterase into Acetic acid and Choline.
On reaching the neuromuscular junction the nerve impulses stimulate the release of about 300 ACh vesicles from the nerve terminals into the synaptic trough. This section describes the normal physiology of the neuromuscular junction.
On close examination several linear dense bars are present on the surface of the axonal terminal. These are believed to be the voltage gated Calcium channels. When the action potentials reach the axonal terminals, these channels allow calcium ions to enter into the terminals in large quantities. The Calcium ions having an attractive influence on the Ach containing vesicles attracts them towards the presynaptic membrane. Eventually the vesicles fuse with the membranes thus releasing ACh into the synaptic trough through the process of Exocytosis. Although much of the information stated above is still speculative, it is widely agreed that the influx of calcium ions is the most effective stimulus for the ACh release. This is further supported by the fact that the ACh vesicles are mainly emptied near the bar bodies.
On the post synaptic membrane lie many ACh gated ion channels. These lie towards the mouths of the sub-neural clefts right below the dense bars where the ACH is released into the troughs. These receptors are large protein complexes with total molecular weights of around 275,000. These complexes are composed of 5 subunit proteins and they penetrate deep into the membranes lying side by side in circles forming a tubular channel. Until ACh attaches to one of the subunits, these channels remain constricted but once ACh molecules attach to them, these channels undergo a conformational change that opens the channels. These channels have a diameter of around 0.5 nm and are large enough to allow the passage of all the important positive ions namely sodium, calcium and potassium whereas the negative ions such as chloride are unable to pass due to the presence of strong negative ions in the mouths of the channels.
Further, it has been found that in practice sodium ions pass through these channels in greater amounts than any other ions for mainly two reasons; firstly there are only two ions in concentrations large enough to be considered significant, Sodium in the extra cellular fluid and potassium in the intracellular fluid. Secondly the presence of a large negative potential of between -80 to -90mV is able to effectively pull sodium into the membranes while simultaneously preventing the efflux of potassium ions.
The overall effect of the ACH entering the post synaptic membranes is that they allow a large number of sodium ions to enter inside the muscle fibers. This causes a large increase in intracellular positive ions which in turn causes a local potential. This local potential is called the end-plate potential and it is this potential that initiates the action potential in the muscle fibers.
Degradation of Acetylcholine
Once Ach gets released into the synaptic trough, it continuously stimulates the Ach receptors for as long as it is present. Thus, it is important to remove it. There are two main mechanisms to remove ACh from the synaptic trough; Firstly As described earlier the enzyme acetylcholinesterase breaks it down into choline and acetic acid, secondly Small quantities of ACh are able to diffuse out of the synaptic trough thus they are unable to stimulate the muscle fibers. Even though ACh remains in the trough for just a few milliseconds it is able to sufficiently stimulate the muscle fibers, it is then removed from the trough thus preventing the fibers from being re-exited after the first action potential.
End plate potential(EPP)
The end plate potential can depolarize the muscle fiber up to +50 to +75 mV. This is way higher than the normal threshold of between 15 to 30 mV. This explains why ACh is able to sufficiently depolarize the muscle fibers in the small time when it is present in order to create an action potential.
Toxins affecting the Neuromuscular Junction
Curare is a drug that acts as a competitive inhibitor of ACh by attaching to the ACh receptors on the post synaptic membrane. Another toxin that acts on the neuromuscular junction is Botulinum however acts on the nerve terminal preventing the release of ACH.
There are several diseases that affect the neuromuscular junction and there are visible variations in their severity as well as their mortality. Further they may be inherited or acquired. Most of them are due to autoimmune disorders or mutations.
Auto immune disorders
- Myasthenia Gravis: It is an autoimmune disorder where anti bodies are produced against either post synaptic muscle-specific kinase or the ACh-receptors igG1. In the seronegative type IgG1 targets low density lipoprotein receptor-related protein competitively inhibiting its ligand from binging to its receptors. There is a lack of solid evidence to whether the seronegative Myasthenia Gravis responds well to standard therapies. Some of the symptoms of myasthenia gravis are Dysphagia, ptosis, Diplopia, muscular weakness, facial paralysis, and difficulty in breathing. Commonly the drug given to myasthenia gravis patients are Cholinesterase inhibitors such as pyridostigmine and neostigmine which prevent ACH breakdown, increasing stimulation. Secondly immuno-suppressants are given in order to decrease the antibody production.
- Lambert Eaton Myasthenic Syndrome(LEMS): It is another auto-immune disorder, this however acts on the pre-synaptic membrane. This produces autoantibodies against the calcium channels thus preventing ACh release. It is characterised by a unique triad of symptoms: weakness of the proximal muscles, Areflexia and Autonomic dysfunction which can lead to dry mouth, constipation etc. Over half of the LEMS cases are associated with a tumor usually a small-cell lung carcinoma and often times it co-exists with Myasthenia Gravis. The first measure treatment is 3,4-diaminopyridine which increases the duration where the voltage gated calcium channels are open and blocks the potassium channels which increases the compound muscular action potential and muscle strength. If 3,4-diaminopyridine does not work prednisone and azathioprine are prescribed.
- Duchenne muscular dystrophy: It is an X-linked recessive disorder that affects 1 out of 3,600–6,000 males. The affected die by the age of 30. It due to lack of production of Dystrophin which is a structural protein. It presents with the following symptoms: elevated Creatine kinase, calf hypertrophy etc. If untreated, it may lead to respiratory distress causing death. There is only symptomatic treatment including the use of steroids.
- Congenital Myasthenic Syndromes(CMS): It is very similar to MG and LEMS. These are autosomal recessive disorders that affect synaptic, presynaptic, and postsynaptic proteins in the neuromuscular junction. These syndromes present symptoms at different ages. During fetal period these can cause fetal Akinesia, during the perinatal period they are known to cause ptosis, arthrogryposis, ophthalmoplegia, hypotonia and breathing or feeding difficulties. These syndromes can also get activated during adolescence or adulthood for example, slow channel syndrome. Their treatment is similar to other neuromuscular disorders with . 3,4-Diaminopyridine being the first line of treatment
Frequently Asked Questions
What are the 3 parts of a neuromuscular junction?
A neuromuscular junction comprises three major components;
- Axonal terminal or presynaptic terminal
- Synaptic cleft
- Postsynaptic membrane i.e. membrane of the muscle fibre
What is the function of the neuromuscular junction?
Neuromuscular junction acts as a communication between the nervous system and the motor system. It transmits nerve impulses from the nerves to the muscle fibres and thus, controls the contraction of muscle fibres.
What type of muscle tissue has neuromuscular junction?
Neouromuscular junctions are seen in the case of the skeletal muscles. These junctions are present at the site where muscle fibres are innervated by nerve fibres.
What type of neurotransmitter is released at the neuromuscular junction?
Acetylcholine is the neurotransmitter that is released by the presynaptic terminal at the neuromuscular junction. This neurotransmitter binds to the postsynaptic membrane and generates an action potential in the muscle fibres.
- Lodish, H; Berk, A; Kaiser, C; Krieger, M; Bretscher, A; Ploegh, H; Amon, A (2000).Molecular Cell Biology(7th ed.). New York, NY: W. H. Freeman and Company. p.695.
- Marieb, E. N., & Hoehn, K. (2014).Human anatomy & physiology.San Francisco, CA: Pearson Education Inc.
The neuromuscular junction (NMJ) is a synaptic connection between the terminal end of a motor nerve and a muscle (skeletal/ smooth/ cardiac). It is the site for the transmission of action potential from nerve to the muscle. It is also a site for many diseases and a site of action for many pharmacological drugs.What are the 7 steps of the neuromuscular junction? ›
- 1) An AP travels down the axon. to the axon terminal.
- 2) Electrical gated calcium channels open. ...
- 3) Calcium causes the vesicles to. ...
- 4) ACH diffuses across the synaptic cleft. ...
- 5) ACH binding opens ion channels. ...
- 6) If the muscle reaches the threshold (-55mv) at the motor end plate. ...
- 7) ACH is broken down by.
The neuromuscular junction—where nerves and muscle fibers meet—is an essential synapse for muscle contraction and movement. Improper function of these junctions can lead to the development of progressive neuromuscular diseases, some of which have no effective treatment (like Lou Gehrig's disease).What are the four parts of a neuromuscular junction? ›
The neuromuscular junction comprises four cell types: the motor neuron, terminal Schwann cell, skeletal muscle fibre and kranocyte, with the motor neuron and muscle fibre separated by a gap called the synaptic cleft.How many steps are in neuromuscular junction? ›
The anatomy of a neuromuscular junction can be divided into three parts: the presynaptic terminal (i.e. the motor neuron) the synaptic cleft. the postsynaptic membrane (i.e. the membrane of the muscle cell).What is the first step of neuromuscular junction? ›
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.Where is the neuromuscular junction formed? ›
The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs.How is the neuromuscular junction formed? ›
The neuromuscular junction (NMJ) is a tripartite synapse that is formed by motor nerve terminals, postjunctional muscle membranes, and terminal Schwann cells (TSCs) that cover the nerve-muscle contact. NMJ formation requires intimate communications among the three different components.What are the 3 main phases of the neuromuscular action potential? ›
It consists of three phases: depolarization, overshoot, and repolarization. An action potential propagates along the cell membrane of an axon until it reaches the terminal button.What is an example of neuromuscular junction? ›
A Skeletal Neuromuscular Junction. The vertebrate neuromuscular junction (Fig. 1) provides an example of a highly specialized neuroeffector synapse, designed for the secure transfer of APs from the spinal motor neurons to skeletal muscle.
Motor neurons from the motor cortex located in the CNS send axons ensheathed in myelin to target muscle cells. A contact between a motoneuron axon and muscle fiber constitutes the neuromuscular junction (NMJ; left panel).What is neuromuscular function? ›
Neuromuscular activity in human physiology is a major adaptive system that facilitates and controls movement and stability in both skeletal and smooth muscle function.
neuromuscular junction, also called myoneural junction, site of chemical communication between a nerve fibre and a muscle cell. The neuromuscular junction is analogous to the synapse between two neurons.How many types of neuromuscular are there? ›
There are three main types: Polymyositis — inflammation is found in many muscles. Inclusion body myositis — muscle is characterized by irregular inclusions—accumulations of misfolded protein. Dermatomyositis — muscle inflammation is accompanied by a skin rash.What are the 5 steps of neurotransmission? ›
Neurotransmitter release from the presynaptic terminal consists of a series of intricate steps: 1) depolarization of the terminal membrane, 2) activation of voltage-gated Ca2+ channels, 3) Ca2+ entry, 4) a change in the conformation of docking proteins, 5) fusion of the vesicle to the plasma membrane, with subsequent ...How many receptors are in the neuromuscular junction? ›
Secondly, within the region of the motor end plate, the sarcolemma of the junctional folds contains 30 to 40 million acetylcholine receptors. These receptors are integral transmembrane proteins that function as an ion channel once activated.Which transmitter is in neuromuscular junction? ›
Acetylcholine (ACh) is the principal neurotransmitter at the vertebrate neuromuscular junction (NMJ), however since the discovery that motoneurons and presynaptic terminals of rodent endplates from the hindlimb muscles extensor digitorum longus (EDL) and soleus are positive for glutamate labelling [1,2], it has been ...Why is neuromuscular junction important? ›
The neuromuscular junction plays a vital role in the function of skeletal muscle. It is responsible for transducting the excitatory electrical impulse from the nervous system to the muscle fiber, resulting in a muscle fiber action.What are the 6 steps of neurotransmission? ›
1) synthesized in neuron, 2) stored in nerve terminal, 3) released in quantities sufficient to affect postsynaptic cell, 4) exogenous application mimics action, 5) mechanism for removal, 6) the presence and use of specific pharmacological blockers and agonists.What are the types of neuromuscular transmission? ›
Depending on the site of dysfunction, NMT disorders are classified into three distinct groups: postsynaptic disorders, presynaptic disorders, and combined presynaptic and postsynaptic disorders.
The neuromuscular system includes all the muscles in the body and the nerves serving them. Every movement the body makes requires communication between the brain and the muscles. The nervous system provides the link between thoughts and actions by relaying messages from the brain to other parts of the body.What causes neuromuscular? ›
Causes of neuromuscular disorders
Some of the causes may include: Genetic mutation. Viral infection. Autoimmune disorder.
Isometric: A muscular contraction in which the length of the muscle does not change. isotonic: A muscular contraction in which the length of the muscle changes. eccentric: An isotonic contraction where the muscle lengthens. concentric: An isotonic contraction where the muscle shortens.What are the 3 muscle movements? ›
Muscle actions are categorized as concentric, eccentric, or isometric depending on whether the muscle shortens, lengthens, or remains the same.What nerve activates the muscle? ›
Alpha motor neurons (also called lower motor neurons) innervate skeletal muscle and cause the muscle contractions that generate movement. Motor neurons release the neurotransmitter acetylcholine at a synapse called the neuromuscular junction.What is the space called between two neurons? ›
synapse, also called neuronal junction, the site of transmission of electric nerve impulses between two nerve cells (neurons) or between a neuron and a gland or muscle cell (effector).What are the benefits of neuromuscular? ›
Other benefits from neuromuscular therapy include an increase of energy levels, improvements in blood circulation, balanced musculoskeletal and nervous systems, lowered body toxin levels, and improvements in overall posture. It can also help you relax and feel less tension days after an appointment.What is neuromuscular process? ›
Neuromuscular transmission (NMT) is a process that permits the central nervous system to control the movement of muscles in the body. Nerve impulses cause the release of a neurotransmitter, acetylcholine (ACh), into the junction between the nerve cell and the muscle cell.What are neuromuscular effects? ›
Some symptoms common to neuromuscular disorders include: Muscle weakness that can lead to twitching, cramps, aches and pains. Muscle loss. Movement issues. Balance problems.What is the gap in the neuromuscular junction called? ›
A neuromuscular junction is a type of synapse; a gap between a motor neurone and the muscle end plate known as the synaptic cleft which is approximately 50 nm wide.
- Amyotrophic lateral sclerosis (ALS)
- Congenital myasthenic syndromes.
- Congenital myopathies.
- Cramp-fasciculation syndrome.
- Elevated creatine kinase.
- Inclusion-body myositis.
- Lambert-Eaton syndrome.
Neuromuscular disorders include a wide-range of diseases affecting the peripheral nervous system, which consists of all the motor and sensory nerves that connect the brain and spinal cord to the rest of the body. Progressive muscle weakness is the predominant condition of these disorders.What are 4 muscle disorders? ›
- Amyotrophic lateral sclerosis (ALS), or motor neuron disease.
- Infantile progressive spinal muscular atrophy.
- Intermediate spinal muscular atrophy.
- Juvenile spinal muscular atrophy.
- Adult spinal muscular atrophy.
The neuromuscular junction (NMJ; AKA myoneural junction or motor end-plate) is the synapse between the nerve and muscle. It has three basic components: 1) presynaptic motor nerve terminal, 2) synaptic space (synaptic cleft), and 3) the postsynaptic surface of the skeletal muscle fiber.What is the definition of the neuromuscular? ›
: of or relating to nerves and muscles. especially : jointly involving or affecting nervous and muscular elements.What is neuromuscular Anatomy? ›
The neuromuscular system includes all the muscles in the body and the nerves serving them. Every movement the body makes requires communication between the brain and the muscles. The nervous system provides the link between thoughts and actions by relaying messages from the brain to other parts of the body.What is neuromuscular junction Byjus? ›
The neuromuscular junction is a highly specialized synapse formed between a motor neuron and a muscle fiber. These junctions convert the electrical impulses generated by the motor neuron into electrical activity in the muscle fibers.What is another word neuromuscular? ›
Alternate Synonyms for "neuromuscular":
contractile organ; contractor; fiber bundle; fibre bundle; fascicle; fasciculus.
The neuromuscular junction plays a vital role in the function of skeletal muscle. It is responsible for transducting the excitatory electrical impulse from the nervous system to the muscle fiber, resulting in a muscle fiber action.Which type of receptor is found in the neuromuscular junction? ›
Nicotinic receptors function within the central nervous system and at the neuromuscular junction. While muscarinic receptors function in both the peripheral and central nervous systems, mediating innervation to visceral organs.