Neuromuscular Transmission Mechanism

Neuromuscular Transmission

• The area of contact between a nerve fiber and a muscle fiber
• Referred to as the motor end plate or myoneural junction
• Contains the synaptic cleft between nerve and muscle fibers
• Acetylcholine (Ach) is released in the synaptic cleft, from the vesicles of the sole feet.
• Mitochondria in the sole feet provide the energy for the acetylcholine release.

Mechanism of Neuromuscular Transmission

• When stimulated, the motor nerve produces and propagates an action potential to the end of the motor neuron.
• Voltage-gated Ca++ channels open in the terminal button.
• Ca++ diffuses into the terminal button from extracellular fluid.
• Calcium ions activate Ca2+-calmodulin dependent protein kinase.
• Synapsin proteins are phosphorylated and anchor acetylcholine vesicles to the cytoskeleton of the presynaptic terminal.
• Acetylcholine vesicles are freed from the cytoskeleton and move to presynaptic neural membrane.
• Vesicles empty acetylcholine into the synaptic space by axocytosis.
• Acetylcholine diffuses across the cleft and binds to specific receptor sites, opening the channel.
• Acetylcholine-gated channels have a large diameter that allow positive ions like sodium, potassium and calcium to move easily.
• Negative ions like chloride do not pass due to strong negative charges at the channel mouth, which repel them.
• An end plate potential initiates an action potential that spreads along the muscle membrane, causing muscle contraction.
• Acetylcholine activates acetylcholine receptors as long as it persists in the synaptic space.
• Acetylcholine is mostly destroyed by the enzyme acetylcholin-esterase, present in the synaptic space between the pre- and postsynaptic membranes.

Properties of Neuromuscular Transmission

• Occurs in one direction: from the neuron (where acetylcholine vesicles are present) to the muscle (where acetylcholine receptors are present).
• Features a 0.5 ms delay for acetylcholine release and action on the muscle membrane.
• Fatigues faster than muscle itself.

Drugs Affecting Neuromuscular Transmission

• Two categories: agents that block or stimulate neuromuscular transmission

Chemical Agents that Block Neuromuscular Transmission

• Curariform drugs are actetylcholine receptor blockers used during surgery to help with skeletal muscle relaxation.
• With curariform drugs, acetylcholine receptors are occupied and acetylcholine cannot combine with them (competitive inhibition)
• Acetylcholine cannot open Na+ and K+ channels, leading to no development of end plate potential, ultimately causing paralysis.
• Botulinum toxin causes food poisoning from canned food contaminated with clostridium botulinum.
• Botulinum toxin blocks the release of acetylcholine from the terminal button.
• Botulinum toxin prevents muscle contraction in response to action potential in the motor neuron.

Chemical Agents that Stimulate Neuromuscular Transmission

• Methacholine, carbacol and nicotine have acetylcholine-like action.
• Methacholine, carbacol & nicotin are not quickly destroyed by cholinesterase, so their action persists longer.
• Neostigmine and physostigmine inactivate acetylcholinesterase in the synapse, preventing it from hydrolyzing acetylcholine.

Myasthenia Gravis

• Affects approximately 1 in 20,000 people.
• Characterized by muscle weakness due to the inability of neuromuscular junctions to effectively transmit signals.
• Is an autoimmune disease involving the loss or blockage of acetylcholine receptors in the neuromuscular junction.
• The end plate potentials in muscle fibers are too weak to initiate opening of voltage-gated sodium channels, preventing muscle fiber depolarization.
• Severe cases can lead to death from respiratory failure through weakness of respiratory muscles.
• Three mechanisms underlie the loss of acetylcholine (Ach) receptors: complement-mediated injury, accelerated Ach receptor degradation, or blockade by antibodies attached to Ach-binding sites.

Myasthenia Gravis Symptoms

• Muscle weakness and fatigability with sustained effort, which improves with rest.
• Commonly affects eye and periorbital muscles.
• Ptosis results from eyelid weakness.
• May cause difficulties in chewing and swallowing.
• Limb weakness is more pronounced in proximal parts.
• Climbing stairs and lifting objects becomes difficult.
• Can affect muscles of the lower face leading to speech impairment as the disease progresses.
• In severe cases, all muscles become weak, leading to death from respiratory failure
• May cause myasthenic crisis, which is a sudden exacerbation of symptoms and weakness that compromises ventilation and requires support.
• Myasthenic crisis is usually triggered by stress, such as infection, emotional upset, pregnancy, alcoholic ingestion, cold exposure, or surgery, or by excessive doses of anticholinesterase drugs.

Myasthenia Gravis Diagnosis

• An immunoassay test detects the presence of antiacetylcholine receptor antibodies in the blood.

Myasthenia Gravis Treatment

• Increase acetylcholine levels by administering acetylcholinesterase inhibitors.
• Inhibit immune-mediated destruction of acetylcholine receptors through steroids, immunosuppressants, and plasma pheresis, to lower antibody levels and suppress the disease.
• Thymectomy to manage myasthenic crisis, addressing immunoglobulin G and T-cell dependent pathogenic antibodies.