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Introduction & Abstract


            Ever wonder what makes a person’s
muscles to contract and relax while doing their daily activities? Neuromuscular
junctions are crucial in processing one’s movements as well as breathing.

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Therefore, it is essential for survival. It is located in the body where the
motor neurons of the nervous system transmit messages from the brain and
instruct the muscles cells to contract or take action. It is also the cause of
the beating of an organism’s heart. Neuromuscular synapse is formed when there
is a connection between the motor neurons and the skeletal muscle fibers. In
other words, a skeletal muscle contracts when it is stimulated by a motor
neuron. After the skeletal muscle is stimulated, a synapse can be found. A
synapse is the space between the motor neuron and the skeletal muscle cell. The
neuromuscular converts the action potential from the presynaptic motor neuron
into the contraction of the postsynaptic muscle fiber which results in a
successfully functioning organism. This paper will demonstrate the
physiological events that is involve with activating neuromuscular junction,
the anatomical structure of the neuromuscular junction, and including the three
potential inhibitors affecting the neuromuscular junction.

Physiological events surrounding the activation
of the neuromuscular junction

            The first physiological event that’s
surrounds the activation of neuromuscular junction is when there is an
excitation of a skeletal muscle fiber which results in the release of the
neurotransmitter ACh. The action potent ion, Calcium, must first enter the
synaptic knob when the nerve signals triggers the opening of the voltage gated
Ca2+ (McKinley, 2015). This will allow the calcium to move from the interstitial
fluid and down the concentration gradient into the synaptic knob. Once the
calcium binds with the synaptic vesicles, it will cause the vesicles to merge
with the plasma membrane (McKinley, 2015). As a result of the the influx of
calcium into the neuron, the neuromuscular ACh is released into the synaptic
cleft.  Acetylcholine is released from
approximately 300 vesicles per nerve signal with each vesicle releasing
thousands of molecules of ACh (McKinley, 2015). The acetylcholine is then
diffused across the synaptic cleft filled with calcium to start binding with
the ACh receptors located in the motor end plate and the motor neuron. This
caused the skeletal muscle fibers to get excited and contract. In other words,
the action potential is being triggered.

            The second physiological event is
the excitation-contraction couplings which is where the muscle contracts. This
event involves sarcolemma, T-tubules, and sarcoplasmic reticulum. There are
three steps that occurs during an excitation-contraction coupling. The first
step is the development of an end-plate potential within the motor end plate.

At this step, the opening of these chemically gated ion channels known as Ach
receptors are triggered during the binding process of ACh and ACh receptors (McKinley,
2015). The opening of these channels allows relatively small amounts of both
Na+ to rapidly diffuse into the skeletal muscle fiber and K+ diffuse out of the
muscle fiber (McKinley, 2015). In other words, sodium ions flows into the
muscle and potassium flows out. This allows an increase in Na+ and K+
permeability of ions which results in a depolarization. However, when there is
a net gain of positive charge on the inside of the muscle fiber, the flow of
both sodium and potassium ions starts to slows down as both of the ions meet (McKinley,
2015). The second step is the initiation and propagation of action potential.

This step is located along the sarcolemma and T-tubules. The motor end plate
triggers an action potential which involves two events. The first event is the
depolarization which caused the inside of the sarcolemma to become positive due
to the large amount of calcium that have entered and also the repolarization
which is when the inside of the sarcolemma turns back to it’s negative resting
membrane potential due to the potassium flowing outwards (McKinley, 2015). The
second event is when the voltage gated potassium channels open and the
potassium ions moves out causing repolarization (McKinley, 2015). Once the
action potential reaches the sarcoplasmic reticulum, the sodium ion channels
opens allowing the sodium ions to diffuse out of the cisternae and into the
sarcoplasm lingering with the think and thin filaments of the myofibrils.

            The third physiological event is the
cross bridge cycling in the sarcomere. Before the muscle contracts, calcium
that is released from the sarcoplasmic reticulum must bind to the troponin in
the thin filaments of the myofibril causing the troponin to change its shape
(1). When a troponin changes shape, the myosin binding sites of the actin are
uncovered allowing cross bridge cycling to begin its process. The cross bridge
cycling consists of four steps: 1. cross bridge formation, 2. power stroke, 3.

release of myosin head from actin, and 4. resetting of myosin head. During
cross bridge formation, the cooked position of the myosin head binds to the the
myosin binding site of the actin and forms a cross bridge between the myosin
and actin (McKinley, 2015). After forming a cross bridge, the myosin head moves
towards the center of the sarcomere while puling along the thin filaments known
as a power stroke (McKinley, 2015). ADP and Pi are then released. ATP starts to
attach to the ATP binding sites of the myosin head causing the myosin head to
be released from the binding site of the actin (McKinley, 2015). To reset the
myosin head, the ATP splits into ADP and Pi to provide enough energy for the
resetting process. The four steps of the cross bridge cycling are then

Anatomical structure of the NMJ

            The neuromuscular junction contains numerous
unique structures based on the age, the type of muscle fibers, and including
the degree of activity. All neuromuscular junctions have similar
characteristics features such as: Schwann cells that forms a cap above the
segment of the nerve membrane; a postsynaptic membrane containing acetylcholine
receptors lies under the nerve terminal known as the post-junctional folds; a
synaptic space lined between the bulb and folds of the basement membrane and a
cytoplasm and cytoskeleton that provides support for the postsynaptic region of
the membrane (Deschenes, 1994). Pre-synaptic and postsynaptic membranes can be
found in the junction synapse. In a pre-synaptic region, the motor neurons
contain long axons which are then branched out creating axon terminal (Deschenes,
1994). Inside the axon terminal contains several components such as
mitochondria, lysosomes, glycogen molecules, and endoplasmic reticulum. Michael
R. Deschenes, a journalist, explained that there are approximately 50 to 70 acetylcholine
containing vesicles per µm^2 of the nerve terminal area (Deschenes, 1994).

In this case, the axon terminal is consisting of an abundance of stored
vesicles containing acetylcholine. Each axon terminal attached to a muscle
fiber are activated commonly known as a motor unit. More than one motor units
often work together to organize the contractions of a muscle. In the
postsynaptic region, acetylcholine receptors are formed at the crests of the
junctional fold (Deschenes, 1994). The folds can be seen as clustered,
stabilized, and even sometimes “finger-like”. These junctional folds are in
direct position with the presynaptic active sites which allows the presynaptic
ACh vesicles to be in direct position with the postsynaptic ACh receptors (Deschenes,
1994). This means that both presynaptic and postsynaptic Ach vesicles and
receptors are quite similar.

Transmitter release inhibitors


            Neurotransmitters enables
communication throughout our brain and body. It sends signals throughout your
body which is responsible for your body to breath, digest and the beating of
your heart. There are two types of neurotransmitter-excitatory and inhibitory.

Excitatory neurotransmitters are what stimulates the brain while the inhibitory
neurotransmitters calm the brain and create balances such as balancing moods. When
a neurotransmitter is released from a presynaptic neuron and binds to a
receptor within postsynaptic neuron, it may result in either excitatory
postsynaptic potential (EPSP) or inhibitory postsynaptic potential (IPSO).

After the neurotransmitters bind to receptors, chemical information is then
converted by receptors and proteins into an electrical information caused by
the activated ion channels (Hyman, 2005). The activation of ion channels will
be able to allow neurotransmitters binding to trigger ion to flow across the
membrane. Either hyperpolarizing negative charges or depolarizing positive
charges may enter the cell depending on which types of channels are triggered (Hyman,
2005). If depolarization enters the cell voltage gated Na+ channels will be
able to open causing an action potential to arrive at the distal end of the
axon (Hyman, 2005). The arrival of action potential will cause a flow of
positive charge which will trigger voltage sensitive Ca2+ channels. That being
said, the amount of calcium entered will cause neurotransmitters to be released
into the synaptic cleft. When neurotransmitters activate cation channels and
are depolarizing, they are considered as excitatory; when neurotransmitters
such as GABA, activate anion channels, they are called inhibitory (Hyman, 2005).

An example of some cation channels are Na+ and Ca2+ which causes a gain of
positively charged ions and examples of anion would be Cl- channels which
causes a gain of negatively charged ions.

Receptor inhibitors


            Pharmacological receptors inhibitors may act as either an agonists
or an antagonist which both responds to the neurotransmitters. An agonist
receptor is a molecule that binds to the receptors and produces an effect
within the cell (Pleuvry, 2002).  An
example of an agonist are certain drugs, neurotransmitters, and hormones. They
help activate receptors to produced a desire response. There are 3 types of
agonists: full agonists, partial agonist, and inverse agonist. A full agonist are
able to produce large responses where the tissue is able to give (Pleuvry, 2002). This means that the agonist may vary in the
amount of response produce due to the amount of receptors available. For
example, the magnitude of response to an agonist is usually proportional to the
fraction of receptors that are occupied (Pleuvry,
2002). A partial agonists have
lower efficiency and cannot produce a maximal response (Pleuvry, 2002). The low efficiency limits the partial
agonists to fully activate the receptors hence the name “partial.” Unlike the
others where they bind to a receptor, inverse agonists give an opposite effect
from an accepted agonist. Agonist receptor can enhance GABA transmission, while
inverse agonists reduces GABA transmission (Pleuvry, 2002).

Because inverse agonists reduce GABA transmission, they will block the effects
of agonists and are dependent on inactive receptors.  

            An antagonist receptor also binds to
the same receptors however it’s differences from agonist is that they cannot
produce a response therefore, it has an ability to block the receptor to an
agonist. An antagonist can either be surmountable or insurmountable. A
surmountable antagonist binds reversibly to the same receptor just like an
agonist but can also reside with the site without the effector mechanism being
activated (Pleuvry, 2002). That being said, surmountable antagonist can
have reversed by increasing or a higher concentration of agonist.

Insurmountable antagonists, however, are not able to be reversed. Though it may
be possible to reverse it with other agonists if the antagonist binds
covalently to the receptor (Pleuvry,



            Acetylcholinesterase inhibitor also known as
anti-cholinesterase is a drug that inhibits acetylcholinesterase enzymes from
breaking down acetylcholine (?olovi?,
2013). That being said, it will
increase the level and duration of the action of neurotransmitter ACh.

Acetylcholinesterase inhibitors can be divided into two groups which are
irreversible and reversible. Reversible inhibitors, competitive or
noncompetitive, mostly have therapeutic applications, while toxic effects are
associated with irreversible AChE activity modulators (?olovi?, 2013).  Since reversible
inhibitors have therapeutic applications, it plays an important role in pharmacological
manipulation to the enzyme activity. This inhibitor is used to treat various
diseases such as myasthenia gravis, bladder distention, glaucoma, however it is
commonly used to treat Alzheimer’s disease. Alzheimer disease are due to the
loss of cholinergic neurons in the brain which can decrease the level of ACh (?olovi?, 2013). There is certainly no cure for AD however, reversible inhibitors
can be used to help with both cognitive and behavioral symptoms such as treat
symptoms related to memory, thinking, language, and decision making. According
to most scientists, the major therapeutic target is the inhibition of the brain
AChE (?olovi?, 2013). Acetylcholinesterase inhibitors drugs
inhibits AChE activity by decreasing the breakdown rate in order to maintain
the ACh level. By maintaining the ACh level, they are able to help boost
cholinergic neurotransmission in the forebrain regions and replace the amount
of loss brain cells. The inhibitor will then be able to take effects in the Alzheimer’s
disease treatment.



conclusion, the reason why the muscles in a body is able to function is because
of the neuromuscular junction. This junction act as a messenger for the
messages that are relayed from the brain to the nervous system. Without these
junctions, the movement request would never get past the brain. However, to
receive a movement on any part of the body is a major and complex process that
includes multiple parts of the body cooperating with each other. What is seem
as a simple movement is not actually simple. A movement has a high amount of micro
actions within the body and these actions are chemicals that are passed through
channels until the signal is received at the designated location. Without these
junctions and receptors, the message would not be receiving by the body and
will have no response. By having damaged or missing receptors, it may be known
as a disease that causes either memory loss, nonresponsive muscle, and loss of
brain cells. However, neuromuscular blocking drugs can be used to temporarily
treat symptoms of muscle weakness. The three physiological events are the
excitation of muscle fibers, excitation contractions couplings, and the cross
bridge cycling in the sarcomere which plays a huge role in activating neuromuscular
junction for muscle contraction. Without these events, the body of any organism
would not be able to properly function yet move at all.

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