We all are familiar with the word Junction.
The most common image that pops up in our minds being:
So, if we link the concept to Nerve- Muscle Physiology, what could the word Junction refer to?
- Define a neuromuscular junction
- Explain the structure of a neuromuscular junction
- Describe the synthesis, storage and release of Acetylcholine
- Understand the sequence of events at neuromuscular junction during a nerve impulse transmission
- Define miniature end plate potential
- Understand the clinical importance and applied aspects of neuromuscular junction
Definition of neuromuscular junction (NMJ)
A neuromuscular junction (or myoneural junction) is a chemical synapse formed by the contact between a motor neuron and a muscle fiber where the motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction.
Structure of a neuromuscular junction
As the axon supplying a skeletal muscle fiber approaches its termination, it loses its myelin sheath and divides into a number of terminal boutons.
The terminal contains many small, clear vesicles that contain acetylcholine, the transmitter at these junctions.
The endings fit into junctional folds, which are depressions in the motor end plate, the thickened portion of the muscle membrane at the junction.
Only one nerve fiber ends on each end plate, with no convergence of multiple inputs.
The space between the nerve and the thickened muscle membrane is comparable to the synaptic cleft at neuron-neuron synapses.
The whole structure is known as the neuromuscular junction.
Since we have seen the structure of NMJ, let us now move on to the events that occur at the NMJ during a nerve transmission.
Have a look at the image below and see if you can enlist the events in the correct order in which they occur during a nerve transmission:
To summarise the events at a neuromuscular junction:
- An impulse arrives in the end of the motor neuron.
- Permeability of the nerve ending to Ca2+ increases leading to Ca2+ entry through voltage gated Ca2+ channels.
- Ca2+ influx triggers a marked increase in exocytosis of the acetylcholine-containing synaptic vesicles.
- The acetylcholine diffuses to nicotinic cholinergic (NM) receptors that are concentrated at the tops of the junctional folds of the membrane of the motor end plate.
- Binding of acetylcholine to these receptors increases the Na+ and K+ conductance, and the resultant influx of Na+ produces a depolarizing potential, the end plate potential.
- The current sink created by this local potential depolarizes the adjacent muscle membrane.
- Opening of more Na+ channels causes the membrane potential to reach the firing level.
- Action potentials are generated on either side of the end plate and are conducted away from the end plate in both directions along the muscle fiber.
- The muscle action potential, in turn, initiates muscle contraction.
- Acetylcholine is then removed from the synaptic cleft by acetylcholinesterase, which is present in high concentration at the neuromuscular junction.
Some more info on Acetylcholine release
An average human end plate contains about 15-40 million acetylcholine receptors.
Each nerve impulse releases acetylcholine from about 60 synaptic vesicles, and each vesicle contains about 10,000 molecules of acetylcholine.
Acetylcholine receptors are divided into 2 main types based on their pharmacologic properties:
- Muscarinic cholinergic receptors
- Nicotinic cholinergic receptors
On the context of neuromuscular junction in skeletal muscle, we are concerned only about nicotinic cholinergic receptors (NM).
Nicotinic cholinergic receptors found in the CNS and autonomic ganglia are of NN type.
Each nicotinic cholinergic receptor is made up of five subunits (two α, one β, one δ, and either one γ or one ε subunit) that form a central channel which, when the receptor is activated, permits the passage of Na+ and other cations.
Each α subunit has a binding site for acetylcholine, and binding of an acetylcholine molecule to each of them induces a conformational change in the protein so that the channel opens.
The opening of the channel causes an increase in the conductance of Na+, and the resulting influx of Na+ produces a depolarizing potential.
Miniature end plate potential
Small quanta (packets) of acetylcholine are released randomly from the nerve cell membrane at rest. Each produces a minute depolarizing spike called a miniature end plate potential, which is about 0.5 mV in amplitude.
The size of the quanta of acetylcholine released in this way varies directly with the Ca2+ concentration and inversely with the Mg2+ concentration at the end plate.
When a nerve impulse reaches the ending, the number of quanta releases increases by several orders of magnitude, and the result is the large end plate potential that exceeds the firing level of the muscle fiber.
Clinical significance of NMJ
Blocking of neuromuscular junction produces muscle relaxation, which is helpful in:
- Surgical operations
- Reducing movements in psychotic patients during electroconvulsive treatment.
Neuromuscular junction can be blocked in two ways:
- By inhibiting the release of acetylcholine from the nerve terminal. Eg: Botulinum toxin.
- By antagonizing the action of acetylcholine on the postsynaptic membrane. Eg: Tubocurarine, suxamethonium, decamethonium etc. Tubocurarine acts by competitive inhibition, ie, it competes with acetylcholine for the nicotinic acetylcholine receptors. Suxamethonium and decamethonium act by persistent depolarization to cause local energy exhaustion with no further ATP generation, resulting in muscle relaxation.
There are also drugs which can enhance the neuromuscular junction. They act in two ways:
- By acetylcholine like action-
- Methacholine, Carbachol, Nicotine
- Unlike acetylcholine they are not destroyed by cholinesterase.
- By inactivating acetylcholinesterase
- Neostigmine, Physostigmine, Diiospropyl fluorophosphate.
- They might even cause death due to laryngeal spasm.
- Diisopropyl fluorophosphate has military potential as ‘nerve gas poison’ since it inactivates cholinesterase for weeks.
Applied aspects of NMJ
Two main diseases of the neuromuscular junction include myasthenia gravis and Lambert-Eaton syndrome.
It is caused by the formation of circulating antibodies to the muscle type of nicotinic cholinergic receptors. These antibodies destroy some of the receptors and bind others to neighbouring receptors, triggering their removal by endocytosis.
The major clinical feature of the disease is muscle fatigue with sustained or repeated activity of the muscles.
Studies show that the postsynaptic membrane has a reduced response to acetylcholine and a 70-90% decrease in the number of receptors per end plate in affected muscles.
There are two major forms of the disease-
- In one form the extraocular muscles are primarily affected.
- In the other form, there is a generalized skeletal muscle weakness. When the diaphragm gets affected, respiratory failure occurs leading to death.
Muscle weakness due to myasthenia gravis improves after a period of rest or after administration of an acetylcholinesterase inhibitor such as neostigmine or pyridostigmine. Cholinesterase inhibitors prevent the metabolism of acetylcholine.
Immunosuppressive drugs like prednisone, azathioprine or cyclosporine can suppress antibody production.
In this relatively rare condition, muscle weakness is caused by an autoimmune attack against one of the voltage- gated Ca2+ channels in the nerve endings at the neuromuscular junction.This decreases the normal Ca2+ influx that causes acetylcholine release.
Proximal muscles of the lower extremities are primarily affected, causing waddling gait & difficulty in raising the arms.
- Immunotherapy- Prednisone administration, plasmapheresis, intravenous immunoglobulin.
- Aminopyridines to facilitate the release of acetylcholine in the neuromuscular junction.
- Acetylcholinesterase inhibitors
A 35 year old woman sees her physician to report muscle weakness in the extraocular muscles & muscles of the extremities. She feels fine when she gets up in the morning, but the weakness begins when she gets active. The weakness is improved by rest. Sensation appears normal. With an acetylcholinesterase inhibitor, she notes immediate return of her muscle strength.
For decades, scientists thought acetylcholine was the only neurotransmitter responsible for controlling how muscles and nerves are wired together during development.
Turns out, they were wrong. Glutamate, the most common neurotransmitter in the brain, also seems to be necessary.
The study shows that the nerves release a molecule that is converted into glutamate, and the glutamate then activates glutamate receptors, notably NMDA receptors, on the muscle.
The glutamate receptor activation modulates the development of the neuromuscular system.
Learn more on the action of glutamate on the postsynaptic muscle membrane, and its clinical significance through the Source link
News Center. Glutamate plays previously unknown role in neuromuscular development. David J. Hill. September 19, 2016. Source link
End of Session
|Botulinum toxin||Brief description on the mechanism of action of botulinum toxin||Botulinum toxin. Wikipedia, the free encyclopedia, 13 Aug 2017, Source link|
- Define neuromuscular junction.
- Define miniature end plate potential.
- Draw a well labeled diagram of neuromuscular junction.
- Write briefly about myasthenia gravis.
- Enlist the sequence of events at NMJ during a nerve impulse transmission.
- Describe the clinical importance of NMJ.
- Lambert-Eaton syndrome.
Watch the video and do a quick recap on neuromuscular junction: