Neuromuscular Transmission Mechanism

• The area of contact occurs between the nerve fiber and muscle fiber
• It is referred to as a motor end plate or myoneural junction
• The space between the nerve and muscle fibers is the synaptic cleft
• Acetylcholine (Ach) is released from the vesicles into the synaptic cleft
• The mitochondria within the sole feet provided the energy for the release of acetylcholine

Mechanism of Neuromuscular Transmission

• When a motor nerve is stimulated, an action potential is produced and propagated to the end of the motor neuron
• Voltage-gated Ca++ channels open in the terminal button
• Ca++ diffuses into the terminal button from the extracellular fluid
• Calcium ions activate Ca2+ - calmodulin-dependent protein kinase
• Synapsin proteins are phosphorylated, anchoring acetylcholine vesicles to the cytoskeleton of the presynaptic terminal
• Acetylcholine vesicles are freed from the cytoskeleton allowing them to move to the presynaptic neural membrane
• Vesicles then release acetylcholine into the synaptic space via axocytosis
• Acetylcholine diffuses across the cleft and binds with specific receptor sites, opening the channel
• Acetylcholine-gated channels allow positive ions such as sodium, potassium, and calcium to move easily through the opening
• Negative ions, such as chloride, cannot pass through due to strong negative charges that repel them
• The end plate potential initiates an action potential that spreads along the muscle membrane, causing muscle contraction
• Acetylcholine, once released into the synaptic space, continues to activate acetylcholine receptors as long as it's present.
• Acetylcholine is destroyed by the enzyme acetylcholinesterase, which is located in the synaptic space

Properties of Neuromuscular Transmission

• It occurs in one direction only
• From the neuron where the acetylcholine vesicles are present in the axon terminals, to the muscle where the acetylcholine receptors are present
• There is a delay of about 0.5 ms in neuromuscular transmission because acetylcholine needs time to be released and act on the muscle membrane
• It fatigues faster than muscle itself

Chemical Agents That Block Neuromuscular Transmission

• Curariform drugs are acetylcholine receptor blockers used during surgery to help with skeletal muscle relaxation
• They occupy the acetylcholine receptors, (competitive inhibition) so acetylcholine cannot combine with these receptors
• The acetylcholine cannot open the Na+& K+ channels, resulting in no development of the end plate potential, no muscle action potential, and paralysis
• Botulinum toxin causes food poisoning resulting from canned food contaminated with Clostridium botulinum
• It blocks the release of acetylcholine from the terminal button in response to an action potential in the motor neuron, causing no muscle contraction

Chemical Agents That Stimulate Neuromuscular Transmission

• Methacholine, Carbacol, and Nicotine have acetylcholine-like action
• These drugs are not destroyed or are destroyed slowly by the cholinesterase enzyme, allowing their action to persist for minutes to hours
• Neostigmine and Physostigmine inactivate acetylcholinesterase in the synapse making it so it no longer hydrolyzes acetylcholine

Myasthenia Gravis

• Myasthenia Gravis auses muscle weakness because of the the inability of the neuromuscular junctions to transmit enough signals
• It is an autoimmune disease, caused by an antibody mediated loss or block of acetylcholine receptors in the neuromuscular junction
• It occurs in about 1 in every 20,000 persons
• The end plate potentials that occur in the muscle fibers are too weak to initiate opening of the voltage-gated sodium channels, preventing muscle fiber depolarization
• If the disease is intense enough, the patient may die of respiratory failure as a result of severe weakness of the respiratory muscles

Causes of Myasthenia Gravis

• Myasthenia Gravis is an autoimmune disease, caused by an antibody mediated loss of acetylcholine receptors in the neuromuscular junction
• Three mechanisms that may cause Myasthenia Gravis: Complement-mediated injury, Accelerated Ach receptor degradation, Blockade of the receptors

Symptoms of Myasthenia Gravis

• Muscle weakness and fatigability with sustained effort improves by rest
• Commonly affects the eye and periorbital muscles, resulting in ptosis due to eyelid weakness
• Chewing and swallowing may be difficult
• Weakness in limb movement is more pronounced in proximal than in distal parts of the extremity
• Climbing stairs and lifting objects are difficult
• The muscles of the lower face are affected, causing speech impairment
• In severe cases, all muscles are weak. Death may result from respiratory failure if the diaphragm and intercostal muscles are affected
• Myasthenic crisis is when a sudden exacerbation of symptoms and weakness occurs
• Muscle weakness becomes severe enough to compromise ventilation
• The myasthenic crisis usually occurs during a period of stress (such as infection, emotional upset, pregnancy, alcoholic ingestion, cold exposure, or surgery) or can be caused by excessive doses of anticholinesterase drugs used in treating the disorder

Diagnosis and Treatment of Myasthenia Gravis

• An immunoassay test can be used to detect the presence of antiacetylcholine receptor antibodies circulating in the blood
• Increase acetyl choline by the administration of acetylcholinesterase inhibitors
• Steroids, immuno-suppressants and plasma pheresis are used to inhibit immune-mediated destruction of acetylcholine receptors
• Thymectomy for the management of myasthenic crisis