Neuromuscular Junction


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 the action potential from the nerve to the muscle. It is also a site for many diseases and a site of action for many pharmacological drugs. In this article, the UNM of skeletal muscle will be discussed.

Matters of interest

NMJ diseases produce muscle weakness through different mechanisms that can affect the presynaptic, synaptic, or postsynaptic portions of the NMJ. The three main diseases involving the NMJ are myasthenia gravis (MG), Lambert-Eaton syndrome (SLE), and botulism.

Physiologic Anatomy of the Neuromuscular Junction

For convenience and understanding, the structure of the Neuromuscular Junction (NMJ) can be divided into three main parts: a presynaptic part (nerve terminal), a postsynaptic part (motor endplate), and an area between the nerve terminal and the motor endplate (synaptic cleft). ).

Nerve Terminal:

A myelinated motor neuron, upon reaching the target muscle, loses its myelin sheath to form a complex of 100-200 branching nerve endings. These nerve endings are called nerve endings or terminal buttons. The nerve terminal membrane has areas of membrane thickening called active zones. The active zones have a family of SNAP proteins (syntaxins and synaptosome-associated protein 25) and rows of voltage-gated calcium (Ca) channels. A nerve terminal also has potassium channels in its membrane and contains mitochondria, endoplasmic reticulum, and synaptic vesicles (SV).

Each SV stores about 5,000-10,000 molecules of acetylcholine (ACh), the neurotransmitter in NMJ. The SVs are concentrated around the active zone. The SV membrane has synaptotagmin and synaptobrevin proteins. These proteins are essential for SV fusion and docking at active sites. Upon the arrival of an action potential at the nerve ending, Ca channels open to cause inflow. The increase in Ca within the nerve terminal causes a series of events that lead to docking of SVs at active sites and exocytosis of ACh from synaptic vesicles into the synaptic cleft.

Synaptic cleft/junctional cleft:

The space between the nerve terminal and the muscle plasma membrane is called the synaptic/junctional cleft and measures approximately 50 nm. It is the site where the presynaptic neurotransmitter ACh is released before it interacts with nicotinic ACh receptors on the motor endplate. The synaptic cleft of the NMJ contains the enzyme acetylcholinesterase, responsible for the catabolism of the released ACh so that its effect on postsynaptic receptors is not prolonged.

Motor End Plate forms the postsynaptic part of NMJ. It is the thickened portion of the muscle’s plasma membrane (sarcolemma) that folds to form depressions called junctional folds. The terminal nerve endings do not penetrate the motor endplate but fit into the junctional folds. The junctional folds have nicotinic ACh receptors concentrated at the top. These receptors are ACh-gated ion channels. The binding of ACh to these receptors opens the channels that allow sodium ions to enter the muscle membrane from the extracellular fluid. This creates an endplate potential and generates and transmits AP to the muscle membrane.


ACh is synthesized at the presynaptic terminal using choline and acetyl-CoA and the enzyme choline acetyltransferase. It then goes through a series of modifications before being packaged in vesicles. Upon depolarization, an action potential travels down the axon, causing voltage-gated calcium channels to open, resulting in an influx of calcium ions into the nerve terminal. This causes the vesicles to migrate towards the nerve terminal membrane and fuse with the active zones.

Different vesicular proteins (SNAP-25, syntaxin) and nerve terminal membrane proteins (synaptobrevin and synaptotagmin) play a role in the fusion of SV to active zones and the exocytosis of ACh in the synaptic cleft. The released ACh subsequently binds to nicotinic ACh receptors at the junctional folds of the motor endplate. The binding of ACh to receptors triggers the opening of ACh-gated ion channels that allow sodium ions to enter the muscle.

Sodium influx changes the postsynaptic membrane potential from -90 mV to -45 mV. This decrease in membrane potential is called the endplate potential. At the NMJ, the endplate potential is strong enough to propagate the action potential over the skeletal muscle membrane surface that ultimately resulting in muscle contraction. To prevent sustained depolarization and muscle contraction, as well as to allow repolarization, acetylcholinesterase metabolizes ACh into its subunits, choline and acetate. Choline can then be reused for ACh synthesis.

Clinical significance

Some of the pharmacology related to the NUM was previously mentioned in the pathophysiology section. The rest will be covered here. There are some chemicals that cause irreversible inhibition of ACh esterase, the enzyme responsible for breaking down ACh into choline and acetic acid in the synaptic cleft. This results in the accumulation of ACh throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Irreversible inhibitors of ACh esterase include Malathion and Parathion. These are commonly used as insecticides. The effects of organophosphates are reversed using a competitive inhibitor such as atropine and/or pralidoxime, which regenerates ACh esterase if administered early enough before enzyme ageing occurs through hydrolysis of the R group.

Others include the central-acting type, such as rivastigmine, galantamine, tacrine, and donepezil. These are used to treat Alzheimer’s dementia. Another pharmacological importance involves the use of NMJ blockers to induce muscle paralysis in anesthesiology. Neuromuscular blockers can be classified as depolarizing (succinylcholine) and non-depolarizing (tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium). Depolarizing agents function as an agonist of the ACh receptor at the NMJ, producing a sustained depolarization that prevents depolarization of the motor endplate, resulting in ACh receptors becoming desensitized and inactivated.

Nondepolarizing agents behave as competitive antagonists and compete with ACh for receptors. In addition, nondepolarizing neuromuscular blockers are the alternative when the patient is a poor metabolizer of pseudocholinesterase (the enzyme that breaks down succinylcholine) or has a mutation in the ryanodine receptor, both of which prolong the action of succinylcholine and can lead to death. a complication of malignant hyperthermia due to sustained muscle contraction.

Direct ACh agonists that bind directly to ACh receptors include bethanechol (used to treat postoperative ileus, urinary retention), carbachol and pilocarpine (both used to treat pupillary muscle constriction glaucoma), and methacholine (Used for a provocation test to diagnose asthma in a patient who is asymptomatic). Lastly, botulinum toxin can be administered medically to relieve sustained muscle contraction in cases of blepharospasm, dystonia, and achalasia.