The neuromuscular junction is the site where presynaptic neurotransmitters such as acetylcholine (ACh) are released before they interact with post-synaptic receptors. It is also the site of metabolism for these neurotransmitters so that their effect on the post-synaptic receptors is not prolonged. Due to our knowledge of the function and physiology of the neuromuscular junction, it is a site of several pharmacologic and disease entities.
Some of the pharmacology regarding the NMJ had been previously mentioned in the pathology section when discussing the treatment of MG using ACh esterase inhibitors to increase the levels of ACh in the synaptic cleft. Another pharmacologic significance involves anesthesiology, as NMJ blockers are used to induce muscle paralysis. These can be divided into depolarizing (succinylcholine) and non-depolarizing (tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium). Depolarizing agents work as an ACh receptor agonist at the NMJ and produce sustained depolarization that prevents repolarization of the motor endplate, resulting in ACh receptors becoming desensitized and inactivated. Non-depolarizing agents behave as competitive antagonists and compete with ACh for receptors. Also, non-depolarizing are the alternative when the patient is a slow metabolizer of pseudocholinesterase (the enzyme that degrades succinylcholine) or have a mutation in the ryanodine receptor, both of which prolong the action of succinylcholine and can lead to the deadly complication of malignant hyperthermia due to sustained muscle contraction.
Other ACh esterase inhibitors include the centrally acting type used to treat Alzheimer dementia such as rivastigmine, galantamine, tacrine, and donepezil.
Irreversible inhibitors of ACh esterase include the organophosphates commonly used as an insecticide, which includes malathion and parathion. These are reversed using a competitive inhibitor such as atropine and/or pralidoxime, which regenerates ACh esterase if given early enough before enzyme aging occurs via hydrolysis of the R group.
A direct agonist of ACh that directly binds to the ACh receptors includes bethanechol (which treats post-op ileus, urinary retention), carbachol, and pilocarpine (both used to treat glaucoma by constriction of the pupillary muscle), and methacholine (challenge test to diagnose asthma in a patient who presents asymptomatically).
Lastly, the release of ACh can be inhibited by the use of botulinum toxin which can be acquired from the bacteria Clostridium botulinum found in canned foods or honey. It can also be given medically to relieve sustained muscle contraction in cases of blepharospasm, dystonia, and achalasia.
In the case of acetylcholine, it is synthesized in the pre-synaptic terminal using choline and acetyl-CoA and the enzyme choline acetyltransferase. It subsequently 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 into the cell. This then triggers the fusion of ACh vesicles with the synaptic membrane, and Ach is released into the synaptic cleft where it diffuses across the synaptic cleft to bind to ACh receptors on the post-synaptic membrane. This triggers changes in permeability of the post-synaptic membrane causing a decrease in membrane potential (from -90 mV to -45 mV) such that action potentials are propagated over the surface of the skeletal muscle resulting in muscle contraction. To prevent sustained depolarization and muscle contraction as well as to allow for repolarization, ACh is metabolized by acetylcholinesterase into its subunits choline and acetate. Choline can then be re-used for the synthesis of ACh.
Our understanding of the neuromuscular junction has allowed us to understand two similar but distinct diseases: myasthenia gravis (MG) and Lambert-Eaton syndrome (LES).
MG is an auto-immune condition (type II hypersensitivity reaction), resulting in the production of auto-antibodies against ACh receptors at the neuromuscular junction and preventing endogenous ACh from interacting with the post-synaptic receptors and inhibiting muscle contraction. As a result, many of the symptoms come as no surprise such as muscle weakness, especially in the extra-ocular muscle as these muscles are in constant use and have a lower density of Ach receptors; difficulty chewing; and limb weakness. These symptoms worsen with use and progress as the day goes on as the ACh in the pre-synaptic cleft becomes depleted and unable to compete with the ACh receptor antibodies. MG is diagnosed by looking for the ACh receptor antibodies (80% to 90% sensitivity), or in cases where clinical suspicion is high but the ACh receptor antibodies are negative, then anti-muscle specific kinase (MUSK) can help make the diagnosis. Treatment in MG is directed at increasing the levels of ACh in the synaptic cleft using ACh esterase inhibitors which prevent the breakdown of ACh in the synaptic cleft and out-compete the antibodies. Examples of ACh esterase inhibitors include neostigmine or pyridostigmine. Other examples of ACh esterase inhibitors that are not used include edrophonium, which is very short-acting, but may be used to aid in diagnosis if the symptom of muscle and extra-ocular weakness abate upon administration; and physostigmine, which is a lipid soluble tertiary amine that crosses the blood-brain barrier. Other medical management includes the use of steroids (prednisone) and steroid-sparing agents (azathioprine, cyclophosphamide, tacrolimus, or mycophenolate). In cases of difficult to control MG refractory to medical therapy and in patients under 60 years of age, a thymectomy to remove a thymoma seen on chest CT may be helpful. Complications of MG include acute flare-ups of myasthenic crises where the patient develops acute muscle weakness and respiratory involvement. These patients are managed with IV immunoglobulins, which bind up the auto-antibodies, or plasmapheresis, which remove the auto-antibodies from the blood.
LES is an auto-immune condition caused by antibodies against voltage-gated calcium (Ca) channels on the pre-synaptic membrane. This prevents Ca from entering the pre-synaptic cell and triggering the fusion of ACh vesicles with the synaptic membrane. Therefore, it essentially prevents the release of ACh into the synaptic cleft and ultimately prevents muscle contraction. As a result, the symptoms of LES are similar to MG such as muscle weakness, difficulty chewing, and fatigue; however, what separates LES from MG is that this muscle weakness improves with use. This is because with repeated attempts at muscle contraction a Ca gradient builds up outside the pre-synaptic Ca channel, eventually allowing the endogenous Cato outcompete the auto-antibodies, enter the pre-synaptic cleft and trigger release of ACh. Similar to MG, LES can be diagnosed by looking for the antibodies. However, the more pressing issue, when LES is diagnosed, is that it is paraneoplastic syndrome and may be a sign of an underlying malignancy, most commonly small cell lung cancer (50% to 70%). Treatment of LES is by addressing the underlying cause, however, because it is associated with small cell lung cancer cure is highly unlikely.
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|Carlson AB,Kraus GP, Physiology, Cholinergic Receptors 2018 Jan; [PubMed]|
|Ploesteanu RL,Nechita AC,Turcu D,Manolescu BN,Stamate SC,Berteanu M, Effects of neuromuscular electrical stimulation in patients with heart failure - review. Journal of medicine and life. 2018 Apr-Jun; [PubMed]|
|Ratliff WA,Saykally JN,Kane MJ,Citron BA, Neuromuscular Junction Morphology and Gene Dysregulation in the Wobbler Model of Spinal Neurodegeneration. Journal of molecular neuroscience : MN. 2018 Sep; [PubMed]|
|Behin A,Le Panse R, New Pathways and Therapeutic Targets in Autoimmune Myasthenia Gravis. Journal of neuromuscular diseases. 2018; [PubMed]|
|Tehran DA,Pirazzini M, Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip. Toxins. 2018 May 10; [PubMed]|
|Lacomis D,Puwanant A, What is in the Neuromuscular Junction Literature? Journal of clinical neuromuscular disease. 2018 Dec; [PubMed]|
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