The nervous system is an elaborate network that enables us to perform functions as vital as breathing or simple as blinking. One of the most fundamental components of this body system is the neuromuscular junction.
The motor neuron nerve terminal and its associated muscle fiber form the highly specialized synapses known as neuromuscular junctions. These synapses are responsible for transforming action potentials produced by the motor neuron into electrical activity in the muscle fibers.
Although the neuromuscular junction is a microscopic complex consisting of only three parts, its importance cannot be understated. As a quintessential component of life and the center of many neurological disease states, it is essential to grasp the fundamental concepts behind the physiology of the neuromuscular junction.
What Is The Neuromuscular Junction?
The neuromuscular junction, or the myoneural junction, is a three-part neuronal unit consisting of the terminal end of a motor neuron, a muscular fiber, and the motor endplate, which separates the first two parts. The role of the neuromuscular junction is to facilitate the transmission of action potentials from motor neurons to the muscle, which ultimately brings about contraction or relaxation of the muscle tissue.
To understand the structure and physiology of the neuromuscular junction, let’s take a deeper look at each section.
The Terminal End Of The Neuromuscular Junction
The terminal end of the motor neuron consists of a large complex of branched nerve endings, which house active zones and calcium ion channels. Like all cells, motor neurons contain standard cell components such as mitochondria, endoplasmic reticulum, and synaptic vesicles.
Nerve endings, also called nerve terminals or terminal boutons, are enclosed in a cellular membrane that thickens in some areas to form active zones. These zones are a dense collection of proteins and voltage-gated calcium ion channels. Active zones are fundamental in releasing neurotransmitters from synaptic vesicles in the motor neuron into the synaptic cleft.
The voltage-gated calcium ion channels in the nerve terminals’ active zones respond to the resting membrane potential change caused by the action potential intended to innervate the muscle tissue. The movement of calcium ions is closely related to the release of the synaptic vesicles into the cleft.
Like all nerve cells, motor neurons are rich in mitochondria. These cellular components are essential for various processes, including adenosine triphosphate (ATP) production, intracellular calcium ion signaling, and the formation of reactive oxygen species. These processes combine to establish the excitability of the cell membrane and facilitate plasticity and neurotransmission.
The endoplasmic reticulum comprises a dense network of interconnected tubules and flattened membrane vesicles responsible for calcium ion homeostasis. This organelle works alongside the mitochondria and calcium ion channels to release synaptic vesicles containing neurotransmitters by modulating the concentration of calcium ions in the motor neuron.
The synaptic vesicles released into the cleft in response to these intracellular changes are specialized sac-like structures that contain neurotransmitters. In motor neurons, these vesicles contain acetylcholine, one of the nervous system’s primary neurotransmitters. The expulsion of acetylcholine from a motor neuron into the synaptic cleft brings about muscular contraction.
The Synaptic Cleft Of The Neuromuscular Junction
The synaptic or junctional cleft is a space of about 50 nanometers between the muscle cell’s plasma membrane and the nerve terminal of the motor neuron. Presynaptic neurotransmitters, such as acetylcholine, are released at this location before interacting with nicotinic acetylcholine receptors on the motor endplate.
Synaptic basal lamina, a particular extracellular matrix, envelopes each muscle cell and passes between the pre-and post-synaptic membranes at the neuromuscular junction. This matrix is essential for the neuromuscular junction’s alignment, structure, and organization.
The acetylcholinesterase enzyme, which is present in the synaptic cleft of the neuromuscular junction, is in charge of breaking down the released acetylcholine so that its effect on the post-synaptic receptors is not prolonged. Ultimately, the action of this enzyme is responsible for the cessation of muscle contraction.
The Motor End Plate Of The Neuromuscular Junction
The motor end plate forms the post-synaptic portion of the neuromuscular junction. The number of muscle cells, or muscle fibers, innervated by one motor neuron can range from a few to many, even though each muscle fiber only gets one motor end plate. A motor unit is the collection of all the muscle fibers that a motor neuron innervates.
A muscle’s motor unit’s size or innervation ratio often decreases as the muscle’s necessity for fine control rises. The mass of the muscle and the rate of contraction has an impact on a motor unit’s size as well. Smaller motor units are frequently found in small muscles, while large motor units typically innervate large, strong muscles that produce significant levels of force.
However, larger muscles can also include small motor units. The small motor units are first engaged for accuracy, whereas the bigger ones are later in the action for enhanced strength.
The muscle plasma membrane’s thicker region, or sarcolemma, is folded to create depressions known as junctional folds. The nerve terminals closely fit the motor end plate to transmit neurotransmitters efficiently.
Thousands of receptors are embedded in the end plate, which are long protein molecules that form channels through the membrane. Nicotinic acetylcholine receptors are clustered at the apex of each junctional fold. These receptors are acetylcholine-gated ion channels that allow the entry of sodium ions from the fluid in the cleft into the muscular membrane.
The movement of sodium ions causes a change in endplate potential, which leads to the transmission of an action potential to the muscle cell’s membrane, followed by muscular contraction.
How Does The Neuromuscular Junction Function?
At first glance, the neuromuscular junction’s intricacy can seem overwhelming. However, breaking down each step in transmitting neurotransmitters between the terminals shines greater clarity on this vastly complex system. Let’s look at how the neuromuscular junction brings about muscular contraction.
The enzyme choline transferase acts on choline and acetyl-CoA to produce acetylcholine in the presynaptic neuron. Acetylcholine then undergoes several changes before being packaged into the synaptic vesicles.
When the motor neuron experiences depolarization, an action potential moves down the axon. The arrival of an action potential results in the opening of voltage-gated calcium channels and a movement of calcium ions into the nerve terminal. As a result, the synaptic vesicles move toward the nerve terminal membrane and join the active zones.
The fusion of the synaptic vesicles to the active zones and the release of acetylcholine into the synaptic cleft are mediated by various vesicular and nerve terminal membrane proteins, namely, synaptobrevin and synaptotagmin.
The nicotinic acetylcholine receptors on the junctional folds of the motor endplate then bind to the released acetylcholine. The acetylcholine-gated ion channels open because of the binding, allowing sodium ions to enter the muscle. The sodium inflow alters the post-synaptic membrane potential from -90 mV to -45 mV.
Endplate potential refers to this drop in membrane potential. Endplate potential in the neuromuscular junction is powerful enough to cause an action potential to spread across the skeletal muscle membrane, which eventually causes muscle contraction.
Acetylcholine is degraded by acetylcholinesterase into its components, choline, and acetate, to avoid prolonged depolarization and muscular contraction and to enable repolarization. The production of acetylcholine can then utilize the choline again.
Disorders Of The Neuromuscular Junction
“Neuromuscular diseases” refers to any condition affecting synaptic communication between a motor neuron and a muscle cell. These illnesses range in severity and fatality and can be inherited or acquired.
In general, autoimmune diseases or mutations are the leading causes of most of these conditions. In the case of neuromuscular illnesses, autoimmune disorders frequently include humoral and B cell mechanisms and are characterized by the inappropriate production of an antibody against a motor neuron or muscle fiber protein that affects synaptic transmission or signaling.
Myasthenia gravis, an autoimmune disease, causes the body to produce antibodies against either the acetylcholine receptor or against a specialized enzyme present in the motor end plate, known as a post-synaptic muscle-specific kinase.
Neonatal myasthenia gravis is an autoimmune disorder that affects children born to mothers diagnosed with myasthenia gravis. This condition can be transferred from the mother to the fetus by transmitting the acetylcholine receptor antibodies through the placenta. Infants born with this disease exhibit weakness or a lack of fetal movement.
Lambert-Eaton myasthenic syndrome, an autoimmune disease, affects the presynaptic portion of the neuromuscular junction. This rare disease can be marked by muscle weakness, autonomic dysfunction, and reduced tendon reflexes. Muscle weakness is caused by pathogenic autoantibodies directed against voltage-gated calcium channels, which reduces acetylcholine release from motor nerve terminals on the presynaptic cell.
Neuromyotonia, known as Isaac’s syndrome, is unlike many other diseases at the neuromuscular junction. Rather than causing muscle weakness, this condition leads to the hyperexcitation of motor nerves. NMT causes this hyperexcitation by producing more prolonged depolarizations by down-regulating voltage-gated potassium channels.
These changes in neurotransmission cause greater neurotransmitter release and repetitive firing. This increase in the firing rate leads to more active transmission and, as a result, greater muscular activity in the affected individual.
Congenital myasthenic syndromes are very similar to myasthenia gravis and Lambert-Eaton myasthenic syndrome in their functions, but the primary difference between the diseases is that genetic mutations cause congenital myasthenic syndromes. These syndromes can present themselves at different times within an individual’s life.
How Do Toxins Affect The Neuromuscular Junction?
Like autoimmune and genetic disease states, various toxins bring about potentially fatal reactions by targeting the neuromuscular junction. You might be surprised to learn how frequently we encounter these toxins. However, advances in modern medicine have allowed us to utilize some of these deadly toxins for our benefit.
Botox is one of the best-known examples of such advancements. By interfering with synaptotagmin and synaptobrevin, botulinum toxin prevents the release of acetylcholine at the neuromuscular junction. As a result, the muscle experiences localized chemical denervation and a brief flaccid paralysis.
The suppression of acetylcholine release begins around two weeks following the injection. The neuronal activity starts to restore function three months after the inhibition partially, and total neuronal function is returned after six months.
Tetanus is a disease brought on by the tetanus toxin, also called tetanospasmin, a potent neurotoxin produced by a bacteria known as Clostridium tetani. The fatal dosage of this toxin has been determined to be roughly one nanogram per kilogram, making it the second-deadliest toxin in the world.
By adhering to and endocytosing into the presynaptic nerve terminal and interfering with protein complexes, it works very similarly to botulinum neurotoxin. Tetanospasmin varies from botulinum neurotoxin in several respects, most notably in its final condition, where it produces a rigid paralysis as opposed to the flaccid paralysis produced by botulinum neurotoxin.
Humans are not the only species that utilize toxins to our benefit. The neuromuscular junction is also impacted by latrotoxin, which is present in the venom of widow spiders. By triggering the release of acetylcholine from the presynaptic cell, this toxin causes calcium to be released from intracellular storage and the formation of pores. This allows calcium ions to enter the system directly.
Both the release of calcium ions and the formation of pores raise the calcium level in the presynaptic cell, which subsequently triggers the release of acetylcholine-containing synaptic vesicles. If left untreated, latrotoxin can result in paralysis and death, as well as extreme pain, muscular tightness, and death.
At the neuromuscular junction, snake venom acts as a toxin that can cause weakness and paralysis. Presynaptic neurotoxins prevent neurotransmitters like acetylcholine from entering the synaptic cleft between neurons. Some of these toxins, nevertheless, are also known to promote the release of neurotransmitters.
The neuromuscular blockade caused by those that limit neurotransmitter release stops signaling molecules from reaching their post-synaptic target receptors. The result is that the person the snake bit has an extreme weakness. Anti-venoms do not work effectively against these neurotoxins. Many of the damaged nerve terminals exhibit tangible symptoms of irreparable physical damage an hour after being inoculated with these toxins, leaving them bereft of synaptic vesicles.
By attaching to the post-synaptic cholinergic receptors, post-synaptic neurotoxins behave differently from presynaptic neurotoxins. This stops the receptors on the post-synaptic cell from interacting with the acetylcholine produced by the presynaptic terminal.
This effectively prevents the opening of sodium channels connected to these acetylcholine receptors, causing a neuromuscular blockade comparable to the effects of presynaptic neurotoxins. The muscles engaged in the impacted connections become paralyzed as a result.
Post-synaptic neurotoxins are more susceptible to anti-venoms than presynaptic neurotoxins, which speed up the toxin’s separation from the receptors and eventually reverse paralysis. These neurotoxins help in research on acetylcholine as well as studies of myasthenia gravis patients.
The neuromuscular junction is a vastly specialized synapse that consists of a motor neuron nerve terminal and its associated muscle fiber. This microscopic system is in charge of transmitting action potentials produced by the motor neuron into electrical activity in the muscle fibers, which ultimately leads to muscular contraction.