A CTUALIZACIÓN DEL PROCESO DE COBRANZA (TO BE)

Muscle fibers are innervated by the axons of motor neuron. Each axon supplies a single muscle fiber, forming one to one relationship called neuromuscular junction. The axon loses its myelin sheath before ending on the muscle fiber. The axon terminal dips into the groove or depression formed by the end plate of the muscle membrane. Between the end plate of muscle membrane and axon terminal, there is a synaptic cleft, which contains basal lamina. It contains

an enzyme acetylcholine esterase, which hydro-lyses acetylcholine.

The axon terminal shows the presence of mitochondria, and a large number of vesicles containing acetylcholine. The muscle membrane facing the axon terminal shows invaginations forming folds called junctional folds (Fig. 3.14).

In these folds, acetylcholine receptors are concentrated.

Synthesis of acetylcholine takes place at the axon terminal with the help of the enzyme choline acetyltransferase. The reaction is as follows

Acetyl CoA Acetyl choline

+ choline choline acetyl transferase

Release of acetylcholine

The arrival of action potential at the axon terminal, opens up voltage gated Ca⁺⁺channels, causing entry of Ca⁺⁺ into the axon terminal. This triggers the subsequent steps in the exocytosis process, which include vesicles moving towards the axon terminal and fusion of the vesicle membrane with the axon terminal membrane to release the transmitter (Fig. 3.15).

Action on end plate

Acetylcholine receptors are found more at the junctional folds of the end plate. They are the nicotinic receptors and have five sub units. Two alpha sub units of the receptor protein has the binding sites for acetylcholine. The receptors contain channels for both Na⁺ and K⁺ and open, when acetylcholine binds to the receptor. Since these channels are activated by the transmitter, they are called ligand gated channels. They do not open by voltage or depolarization of the membrane. The opening of both the channels in the receptor, causes movement of ions. The electrochemical gradient for Na⁺ to enter is far greater than the gradient for K⁺ ion to leave and hence depolarization of muscle membrane occurs.

The membrane potential falls from - 90 mv to - 60 mv (towards threshold level). This is a graded, nonpropagatory electrical potential known as end plate potential (EPP) (Fig. 3.16).

When action potential arrives at the axon terminal, there will be release of acetylcholine

Fig. 3.14: Neuromuscular junction

Fig. 3.15: Neuromuscular transmission

→

→ →

→

→

from 200 to 300 vesicles and the depolarization of the end plate (EPP) is sufficient to reach the threshold level of firing forming a propagated action potential. The action potential spreads to the contiguous end plate membrane.

It has been found that each vesicle, when fuses with the axon terminal, releases approxi-mately 5000 to 10,000 acetylcholine molecules.

Even when there is no nerve stimulation, there is a spontaneous release of acetylcholine called quantal release. This release occurs from a single vesicle. The quantal release of acetylcholine can cause depolarization of the end plate membrane to only 1 mv. These potentials cannot reach the threshold level of firing and they are called miniature end plate potentials (MEPP).

Quantal release of acetylcholine helps to maintain the integrity of muscle fiber.

Acetylcholine inactivation

The enzyme acetylcholine esterase, present in the basal lamina, hydrolyzes acetyl choline into choline and acetic acid. The reaction proceeds as follows

Acetylcholine esterase

Acetylcholine Acetic acid +

Choline Inactivation of acetylcholine at the neuro-muscular junction is necessary to prevent continuous stimulation of muscle contraction.

Choline uptake at the axon terminal is

signi-ficant, as the choline, after its uptake is reutilized for the synthesis of acetylcholine. Agents, which block the uptake of choline at the axon terminal will result in reduced synthesis of acetylcholine and this mechanism can be used to minimise the action of acetylcholine at the end plate.

Blocking of neuromuscular transmission Neuromuscular transmission is blocked by drugs, poisons and toxins.

Curare: It is an alkaloid and a poisonous substance. When injected into the body, it binds to acetylcholine receptors by displacing the transmitter (competitive inhibition). Although, curare binds to the acetylcholine receptors, it does not cause depolarization of the end plate.

(non depolarizing type). If sufficient number of receptors are occupied by curare, it will lead to muscular paralysis including respiratory muscles and results in death.

Succinyl choline: It is also a neuromuscular blocking agent. It causes depolarization of the end plate initially, but, later inactivates Na⁺channels and blocks the neuromuscular transmission. This depolarizing type of agent is used to cause muscle relaxation during surgery.

Botulinum toxin: It inhibits the release of acetylcholine from vesicles and thereby prevents transmission.

Alpha bungarotoxin: It is a snake venom obtained from cobra. It binds irreversibly to the nicotinic receptors of the acetylcholine at the end plate. When the venom enters the body, it will get attached to the end plate acetylcholine receptors and causes paralysis of muscles, including respiratory muscles and results in death.

Acetylcholine esterase inhibitors

They are two types namely reversible and irreversible. They help to increase the concent-ration of acetylcholine at the end plate. Rever-sible inhibitors include neostigmine and physostigmine.

Fig. 3.16: End plate potential and the development of action potential when EPP reaches the threshold level of firing

The irreversible group of agents include insecticide and nerve gas poisons.

Diseases affecting neuromuscular transmission

Myasthenia gravis

It is an autoimmune disease, in which the body produces antibodies against its own acetyl-choline receptor protein. When acetylacetyl-choline receptors are blocked by autoimmune antibodies, the released actylcholine cannot act on the receptors. This results in blocking of transmission and leads to muscle weakness and paralysis. It has been observed that thymus gets enlarged, showing its link in the pathophy-siology of myasthenia gravis. The disease is treated by the administration of anticholine esterases like neostigmine and physostigmine, which increase the concentration of acetylcholine at the end plate. Increased concentrations of acetylcholine at the end plate, will help to displace the autoantibodies from the receptors.