Neuromuscular Junction


Neuromuscular Junction Part 1


Neuromuscular Junction Part 2

General Points

Information to the skeletal muscle comes through motor neuron and it is connected with the spinal cord.

Anterior horn in the spinal cord are motor horn where the motor neuron comes out which are destined to supply the neuromuscular junction.

Muscle is innervated and stimulated by the ending part of neuron called as nerve terminal.

Action Potential are electrical signals which comes from the spinal cord, travelling along the membrane of motor neuron, when they reach at the nerve ending they lead to release of chemical neurotransmitter which binds to receptor on muscle membrane called as motor end plate.

Motor End Plate is the part of muscle membrane which is connected with the motor neuron. It receives the chemical messages from nerve ending and will convert into electrical messages.

Neuromuscular transmission transfers the information from motor nerve ending to the motor end plate.

Neuromuscular Junction is a point where neurons and muscle meet.


Activity In Nerve Ending

Chemical substances which stored in the nerve endings are called neurotransmitters. They release and transfer information to the post synaptic membrane.

Note: Synapse is the meeting surface of two cells where information from one cell transfers to the next .

Neuromuscular junction is actually a synapse between the neuronal membrane and muscular membrane, where there is tremendous exchange of neurotransmitters. Hence, this neuromuscular junction is also referred as chemical synapse.

Chemical substance acetylcholine enclosed in synaptic vesicles at the motor nerve ending, and these vesicles are synthesized in the cell body of neuron.

NOTE: Cell body of the neuron having mRNA which synthesizes special type of proteins that transported to the nerve endings and attach with the vesicle membrane. One of these special type of proteins help acetylcholine to enter synaptic vesicles while the other protein helps vesicles to attach with the nerve ending membrane.


A) Formation of Acetylcholine.

Nerve Endings have special proteins in their membrane called choline transporters, which transports the choline from the extracellular fluid into the nerve ending. Mitochondria, present in the nerve endings synthesizes acetyl CoA. This acetyl CoA and choline fuses together to make acetylcholine with the help of an enzyme called choline Acetyltransferase. Acetylcholine transported to the vesicles with the help of protein transporter presents on the surface of vesicle membrane.


B) Generation of Action Potential

Sodium enters into the nerve ending through the voltage gated sodium channels which brings RMP to -70mv and depolarization occurs. After depolarization membrane potential becomes +10mv.

There are calcium sensitive proteins present on the nerve membrane and vesicles. These calcium sensitive proteins help to bind vesicles to the nerve membrane. As soon as nerve ending depolarizes it activates the voltage sensitive calcium channels. Calcium influx starts which leads to binding of vesicles to the cell membrane. After binding, by the process of exocytosis acetylcholine releases into neuromuscular junction.

Note: Calcium sensitive protein present on the vesicles is called as synaptobrevin and protein present on the nerve membrane is called as syntaxin.


Activity In Synaptic Cleft

The gap between the presynaptic membrane on the nerve ending and the post synaptic membrane on the motor end plate is called as synaptic cleft. Acetylcholine moves from pre synaptic membrane to the post synaptic membrane by the process of diffusion.


Activity In Motor End Plate

Acetylcholine sensitive channels are present on the post synaptic membrane. These are ligand gated channels and as they become activated by the acetylcholine attachment leads to the influx of sodium and efflux of potassium. Before the opening of channel the muscle has RMP of -80mv, but after the influx of sodium the RMP moves from -80mv to 0mv and depolarizes the membrane. As this local potential is formed at end plate, it is called as end plate potential (EPP).

Miniature end plate potential (MEPP) is a small end plate potential produced by the release of Acetylcholine from a single vesicle and produces small stimulation of cholinergic receptor so small amount of sodium influx occurs and cause very less fluctuation in RMP. In NM transmission many vesicles are released together to produce MEPP which are added together to form full end plate potential.

End Plate Potential will take RMP to the threshold potential. As muscle membrane has many voltage gated sodium channels. On the threshold potential, voltage gated sodium channels will open and heavy amount of sodium influx occurs due to activation of these channels.

This depolarizing current will take the neighboring part of muscle membrane to the threshold and it will go under depolarization. So the wave of depolarization will go all over the muscle membrane.

Hence, the action potential of the neuron through the neuromuscular junction reaches the muscle.


Fate of acetylcholine

Special enzyme Acetylcholinesterase present in the extracellular matrix of neuromuscular junction, they will break acetylcholine into acetyl CoA and choline.

Acetyl CoA will diffuse into blood and choline will reuptake by nerve endings. Mitochondria present in the nerve ending can produce acetyl CoA but not choline.


Clinical Problems:

1) Myasthenia Gravis.

In this disease the person develops progressive weakness of muscle and even very small activity can cause fatigue a lot.

So muscle weakness and easy fatigability are cardinal signs of this disease.

This disease is caused by the formation of auto antibodies against the nicotinic cholinergic receptors present on the post synaptic membrane, due to this AcH fails to bind with the receptor and hence neurotransmission will not occur.

Treatment: : Acetylcholinesterase Inhibitors ( Pyridostigmine , Neostigmine)

These drugs will inhibit the acetylcholinesterase inhibitor enzyme and causes the increase in amount of acetylcholine, so AcH will work on the remaining receptors and causes the influx of sodium and action potential will start.

2) Eaten Lambart Syndrome (E.L.S)

In this disease there is a formation of autoantibodies against calcium channels so no ca++ influx will occur that decreases the release of AcH that leads to no neurotransmission.

Note: ELS improves gradually with the activity while the M.G worsens with the activity

ELS acts on pre synaptic membrane and M.G acts on post synaptic membrane.


Drugs Acting On Neuromuscular Junction:

1) Hemicholinium

This drug will block the uptake of choline and progressively the AcH formation will be reduced and eventually there would be no enough release of AcH for the generation of action potential and hence no neurotransmission will occur.


2) Vesamicole

It acts on the vesicles and do not allow the uptake of AcH and vesicles becomes under filled with the Ach , so there would be less release of Ach causing less neurotransmission to occur, resulting in muscle weakness.


3) Botilinium Toxin

It is a proteolytic enzyme produced by the aerobic bacteria and released as exotoxin. These toxins bind with the choline uptake system and through this come to nerve ending.

At nerve ending they inhibit binding of synaptobrevin with syntaxin and hence vesicular membrane does not fuse with the nerve membrane resulting in neurotransmission blockage. This toxin causes Floppy Baby Syndrome.


4) D-Tubocuranin

It binds with the nicotinic cholinergic receptors present on the post synaptic membrane and hence neurotransmission fails to occur. It is a hypo polarizing neuromuscular blocker. It is also used with general anesthesia to relax the muscles of the patient to be operated.


5) Succinylcholine

This drug will cause prolong stimulation of the cholinergic receptors causing an increase in influx of sodium. Prolonged depolarization leads to inactivation of voltage gated sodium channels. These are depolarizing neuromuscular blockers.

Note: If we keep the RMP of excitable tissues near the threshold for a very long time, then most of the Na+ gated sodium channels will stuck into inactive stage.


 

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