End-plate potential

End plate potentials (EPPs) are the voltages which cause depolarization of
skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic
membrane in the neuromuscular junction. They are called "end plates" because
the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.
When an action potential reaches the axon terminal of a motor neuron, vesicles
carrying neurotransmitters (mostly acetylcholine) are exocytosed and the
contents are released into the neuromuscular junction. These neurotransmitters
bind to receptors on the postsynaptic membrane and lead to its depolarization. In
the absence of an action potential, acetylcholine vesicles spontaneously leak into
the neuromuscular junction and cause very small depolarizations in the
postsynaptic membrane. This small response (~0.4mV)[1] is called a miniature
end plate potential (MEPP) and is generated by one acetylcholine-containing A sample endplate potential (EPP;
vesicle. It represents the smallest possible depolarization which can be induced an average of 10 single EPPs) is
in a muscle. shown at the top, and sample
miniature endplate potentials
(mEPPs) are shown at the bottom.
Note the differences in the scales on
Contents the X- and Y-axes. Both are taken
from recordings at the mouse
Neuromuscular junction neuromuscular junction.
Acetylcholine
Ion channels
Presynaptic membrane
Postsynaptic membrane
Initiation
Synaptic vesicles
Miniature end plate potentials (MEPPs)
Threshold potential ("All or None")
Action potential phases
Clinical applications
See also
References
External links

Neuromuscular junction
The neuromuscular junction is the synapse that is formed between an alpha motor neuron (α-MN) and the skeletal muscle fiber.
In order for a muscle to contract, an action potential is first propagated down a nerve until it reaches the axon terminal of the
motor neuron. The motor neuron then innervates the muscle fibers to contraction by causing an action potential on the
postsynaptic membrane of the neuromuscular junction.

Acetylcholine
End plate potentials are produced almost entirely by the
neurotransmitter acetylcholine in skeletal muscle.
Acetylcholine is the second most important excitatory
neurotransmitter in the body following glutamate. It
controls the somatosensory system which includes the
senses of touch, vision, and hearing. It was the first
neurotransmitter to be identified in 1914 by Henry Dale.
Acetylcholine is synthesized in the cytoplasm of the neuron
from choline and acetyl-CoA. Choline acyltransferase is the
enzyme that synthesizes acetylcholine and is often used as a
marker in research relating to acetylcholine production.
Neurons that utilize acetylcholine are called cholinergic
neurons and they are very important in muscle contraction,
memory, and learning.[2]

Ion channels
The polarization of membranes is controlled by sodium,
potassium, calcium, and chloride ion channels. There are
two types of ion channels involved in the neuromuscular
junction and end plate potentials: voltage-gated ion channel
and ligand-gated ion channel. Voltage gated ion channels
are responsive to changes in membrane voltage which
cause the voltage gated ion channel to open and allows
certain ions to pass through. Ligand gated ion channels are
responsive to certain molecules such as neurotransmitters.
The binding of a ligand to the receptor on the ion channel
protein causes a conformational change which allows the Signal transmission from nerve to muscle at the motor
passing of certain ions. end plate.

Presynaptic membrane
Normally the resting membrane potential of a motor neuron is kept at -70mV to -50 with a higher concentration of sodium
outside and a higher concentration of potassium inside. When an action potential propagates down a nerve and reaches the axon
terminal of the motor neuron, the change in membrane voltage causes the calcium voltage gated ion channels to open allowing for
an influx of calcium ions. These calcium ions cause the acetylcholine vesicles attached to the presynaptic membrane to release
acetylcholine via exocytosis into the synaptic cleft.[3]

Postsynaptic membrane
EPP are caused mostly by the binding of acetylcholine to receptors in the postsynaptic membrane. There are two different kinds
of acetylcholine receptors: nicotinic and muscarinic. Nicotinic receptors are ligand gated ion channels for fast transmission. All
acetylcholine receptors in the neuromuscular junction are nicotinic. Muscarinic receptors are G protein-coupled receptors that use
a second messenger. These receptors are slow and therefore are unable to measure a miniature end plate potential (MEPP). They
are located in the parasympathetic nervous system such as in the vagus nerve and the gastrointestinal tract. During fetal
development acetylcholine receptors are concentrated on the postsynaptic membrane and the entire surface of the nerve terminal
in the growing embryo is covered even before a signal is fired. Five subunits consisting of four different proteins from four
different genes comprise the nicotinic acetylcholine receptors therefore their packaging and assembly is a very complicated
process with many different factors. The enzyme muscle-specific kinase (MuSK) initiates signaling processes in the developing
postsynaptic muscle cell. It stabilizes the postsynaptic acetylcholine receptor clusters, facilitates the transcription of synaptic
genes by muscle fiber nuclei, and triggers differentiation of the axon growth cone to form a differentiated nerve terminal.[4]
Substrate laminin induces advanced maturation of the acetylcholine receptor clusters on the surfaces of myotubes.[5]

Initiation

Synaptic vesicles
All neurotransmitters are released into the synaptic cleft via exocytosis from synaptic vesicles. Two kinds of neurotransmitter
vesicles exist: large dense core vesicles and small clear core vesicles. Large dense core vesicles contain neuropeptides and large
neurotransmitters that are created in the cell body of the neuron and then transported via fast axonal transport down to the axon
terminal. Small clear core vesicles transport small molecule neurotransmitters that are synthesized locally in the presynaptic
terminals. Finalized neurotransmitter vesicles are bound to the presynaptic membrane. When an action potential propagates down
the motor neuron axon and arrives at the axon terminal, it causes a depolarization of the axon terminal and opens calcium
channels. This causes the release of the neurotransmitters via vesicle exocytosis.

After exocytosis, vesicles are recycled during a process known as the synaptic vesicle cycle. The retrieved vesicular membranes
are passed through several intracellular compartments where they are modified to make new synaptic vesicles. They are then
stored in a reserve pool until they are needed again for transport and release of neurotransmitters.

Unlike the reserve pool, the readily releasable pool of synaptic vesicles is ready to be activated. Vesicle depletion from the readily
releasable pool occurs during high frequency stimulation of long duration and the size of the evoked EPP reduces. This
neuromuscular depression is due to less neurotransmitter release during stimulation. In order for depletion not to occur, there
must be a balance between repletion and depletion which can happen at low stimulation frequencies of less than 30 Hz.[6]

When a vesicle releases its neurotransmitters via exocytosis, it empties its entire contents into the synaptic cleft. Neurotransmitter
release from vesicles is therefore stated to be quantal because only whole numbers of vesicles can be released. In 1970, Bernard
Katz from the University of London won the Nobel Prize for Physiology or Medicine for statistically determining the quantal size
of acetylcholine vesicles based on noise analysis in the neuromuscular junction. Using a book on mechanical statistics, he was
able to infer the size of individual events going on at the same time.

The synaptic vesicles of acetylcholine are clear core synaptic vesicles with a diameter of 30 nm. Each acetylcholine vesicle
contains approximately 5000 acetylcholine molecules. The vesicles release their entire quantity of acetylcholine and this causes
miniature end plate potentials (MEPPs) to occur which are less than 1mV in amplitude and not enough to reach threshold.[7]

Miniature end plate potentials (MEPPs)

Miniature end plate potentials are the small (~0.4mV) depolarizations of the postsynaptic terminal caused by the release of a
single vesicle into the synaptic cleft. Neurotransmitter vesicles containing acetylcholine collide spontaneously with the nerve
terminal and release acetylcholine into the neuromuscular junction even without a signal from the axon. These small
depolarizations are not enough to reach threshold and so an action potential in the postsynaptic membrane does not occur.[8]
During experimentation with MEPPs, it was noticed that often spontaneous action potentials would occur, called end plate spikes
in normal striated muscle without any stimulus. It was believed that these end plate spikes occurred as a result of injury or
irritation of the muscles fibers due to the electrodes. Recent experiments have shown that these end plate spikes are actually
caused by muscle spindles and have two distinct patterns: small and large. Small end plate spikes have a negative onset without
signal propagation and large end plate spikes resemble motor unit potentials (MUPs). Muscle spindles are sensory receptors that
measure muscle elongation or stretch and relay the information to the spinal cord or brain for the appropriate response.[9]
Threshold potential ("All or None")
When an action potential causes the release of many acetylcholine vesicles, acetylcholine diffuses across the neuromuscular
junction and binds to ligand-gated nicotinic receptors (non-selective cation channels) on the muscle fiber. This allows for
increased flow of sodium and potassium ions, causing depolarization of the sarcolemma (muscle cell membrane). The small
depolarization associated with the release of acetylcholine from an individual synaptic vesicle is called a miniature end-plate
potential (MEPP), and has a magnitude of about +0.4mV. MEPPs are additive, eventually increasing the end-plate potential
(EPPs) from about -100mV up to the threshold potential of -60mV, at which level the voltage-gated ion channels in the
postsynaptic membrane open, allowing a sudden flow of sodium ions from the synapse and a sharp spike in depolarization. This
depolarization voltage spike triggers an action potential which propagates down the postsynaptic membrane leading to muscle
contraction. It is important to note that EPPs are not action potentials, but that they trigger action potentials. In a normal muscular
contraction, approximately 100-200 acetylcholine vesicles are released causing a depolarization that is 100 times greater in
magnitude than a MEPP. This causes the membrane potential to depolarize +40mV (100 x 0.4mV = 40mV) from -100mV to
-60mV where it reaches threshold.[7]

Action potential phases

Once the membrane potential reaches threshold, an action potential occurs and causes a sharp spike in membrane polarity. There
are five phases of an action potential: threshold, depolarization, peak, repolarization, and hyperpolarization.

Threshold is when the summation of MEPPs reaches a certain potential and induces the opening of the voltage-gated ion
channels. The rapid influx of sodium ions causes the membrane potential to reach a positive charge. The potassium ion channels
are slower-acting than the sodium ion channels and so as the membrane potential starts to peak, the potassium ion channels open
and causes an outflux of potassium to counteract the influx of sodium. At the peak, the outflux of potassium equals the influx of
sodium, and the membrane does not change polarity.

During repolarization, the sodium channels begin to become inactivated, causing a net efflux of potassium ions. This causes the
membrane potential to drop down to its resting membrane potential of -100mV. Hyperpolarization occurs because the slow-acting
potassium channels take longer to deactivate, so the membrane overshoots the resting potential. It gradually returns to resting
potential and is ready for another action potential to occur.

During the action potential before the hyperpolarization phase, the membrane is unresponsive to any stimulation. This inability to
induce another action potential is known as the absolute refractory period. During the hyperpolarization period, the membrane is
again responsive to stimulations but it requires a much higher input to induce an action potential. This phase is known as the
relative refractory period.

Once the action potential has finished in the neuromuscular junction, the used acetylcholine is cleared out of the synaptic cleft by
the enzyme acetylcholinesterase. Several diseases and problems can be caused by the inability of enzymes to clear away the
neurotransmitters from the synaptic cleft leading to continued action potential propagation.[10]

Clinical applications
Current research is attempting to learn more about end plate potentials and their effect on muscle activity. Many current diseases
involve disrupted end plate potential activity. In Alzheimer patients, beta amyloid attaches to the acetylcholine receptors and
inhibits acetylcholine binding. This causes less signal propagation and small EPPs that do not reach threshold. By analyzing brain
processes with acetylcholine, doctors can measure how much beta amyloid is around and use it to judge its effects on
Alzheimer's.[11] Myasthenia gravis is an autoimmune disease, where the body produces antibodies targeted against the
acetylcholine receptor on the postsynaptic membrane in the neuromuscular junction. Muscle fatigue and weakness, worsened
with use and improved by rest, is the hallmark of the disease. Because of the limited amount of acetylcholine receptors that are
 available for binding, symptomatic treatment consists of using an
acetylcholinesterase inhibitor to reduce the breakdown of acetylcholine in the
neuromuscular junction, so that enough acetylcholine will be present for the small
number of unblocked receptors. A congenital abnormality caused by a deficiency
in end-plate acetylcholine esterase (AChE) might be a pathophysiologic
mechanism for myasthenic gravis. In a study on a patient with AChE deficiency,
doctors noted that he had developed severe proximal and truncal muscle weakness
Patient with myasthenia gravis with jittering in other muscles. It was found that a combination of the jitter and
showing typical symptom of eyelid blocking rate of the acetylcholine receptors caused a reduced end-plate potential
droop similar to what is seen in cases of myasthenia gravis.[12] Research of motor unit
potentials (MUPs) has led to possible clinical applications in the evaluation of the
progression of pathological diseases to myogenic or neurogenic origins by
measuring the irregularity constant related. Motor unit potentials are the electrical signals produced by motor units that can be
characterized by amplitude, duration, phase, and peak, and the irregularity coefficient (IR) is calculated based on the peak
numbers and amplitudes.[13] Lambert-Eaton myasthenic syndrome is a disorder where presynaptic calcium channels are
subjected to autoimmune destruction which causes fewer neurotransmitter vesicles to be exocytosed. This causes smaller EPPs
due to less vesicles being released. Often the smaller EPPs do not reach threshold which causes muscle weakness and fatigue in
patients. Many animals use neurotoxins to defend themselves and kill prey. Tetrodotoxin is a poison found in the certain
poisonous fishes such as pufferfish and triggerfish which blocks the sodium ion channels and prevents an action potential on the
postsynaptic membrane. Tetraethylammonium found in insects blocks potassium channels. Alpha neurotoxin found in snakes
binds to acetylcholine receptors and prevents acetylcholine from binding. Alpha-latrotoxin found in black widow spiders causes a
massive influx of calcium at the axon terminal and leads to an overflow of neurotransmitter release. Botulinum toxin produced by
the bacteria Clostridium botulinum is the most powerful toxic protein. It prevents release of acetylcholine at the neuromuscular
junction by inhibiting docking of the neurotransmitter vesicles.

See also
Acetylcholine
Action potential
Alpha-latrotoxin
Alzheimer's disease
Botulinum toxin
Motor neuron
Muscarinic receptors
Myasthenia gravis
Neuromuscular junction
Neurotransmitter
Nicotinic receptors
Skeletal muscle
Synaptic vesicle
Tetraethylammonium
Tetrodotoxin

References
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0-8089-2449-4.
 2. Kimura Y; Oda Y; Deguchi T; Higashida H. (1992). "Enhanced acetylcholine secretion in neuroblastoma X glioma
hybrid NG108-15 cells transfected with rat choline-acetyltransferase CDNA". FEBS Letters. 314 (3): 409–412.
doi:10.1016/0014-5793(92)81516-O (https://doi.org/10.1016%2F0014-5793%2892%2981516-O). PMID 1468577
(https://www.ncbi.nlm.nih.gov/pubmed/1468577).
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mammalian neuromuscular junction formation". Journal of Neuroscience. 28 (13): 3333–3340.
doi:10.1523/JNEUROSCI.5590-07.2008 (https://doi.org/10.1523%2FJNEUROSCI.5590-07.2008).
PMID 18367600 (https://www.ncbi.nlm.nih.gov/pubmed/18367600).
4. Cole RN, Reddel SW, Gervasio OL, Phillips WD (2008). "Anti-MuSK patient antibodies disrupt the mouse
neuromuscular junction". Annals of Neurology. 63 (6): 782–789. doi:10.1002/ana.21371 (https://doi.org/10.100
2%2Fana.21371). PMID 18384168 (https://www.ncbi.nlm.nih.gov/pubmed/18384168).
5. Teressa G, Prives J (2008). "Cell culture-based analysis of postsynaptic membrane assembly in muscle cells" (htt
ps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683546). Biological Procedures Online. 10 (1): 58–65.
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es/PMC2683546). PMID 19461953 (https://www.ncbi.nlm.nih.gov/pubmed/19461953).
6. Van Lunteren E, Moyer M (2005). "Modulation of biphasic reate of end-plate potential recovery in rat diaphragm".
Muscle & Nerve. 31 (3): 321–330. doi:10.1002/mus.20245 (https://doi.org/10.1002%2Fmus.20245).
PMID 15654692 (https://www.ncbi.nlm.nih.gov/pubmed/15654692).
7. Takeda T, Sakata A, Matsuoka T (1999). "Fractal dimensions in the occurrence of miniature end-plate potential in
a vertebrate neuromuscular junction". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 23 (6):
1157–1169. doi:10.1016/S0278-5846(99)00050-0 (https://doi.org/10.1016%2FS0278-5846%2899%2900050-0).
8. Sellin LC, Molgo J, Thornquist K, Hansson B, Thesleff S (1996). "On the possible origin of giant or slow-rising
miniature end plate potentials at the neuromuscular junction". Pflügers Archiv: European Journal of Physiology.
431 (3): 325–334. doi:10.1007/BF02207269 (https://doi.org/10.1007%2FBF02207269).
9. Partanen J (1999). "End plate spikes in the human electromyogram. Revision of the fusimotor theory". Journal of
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10. Purves D, Augustine G, et al. "Electrical Signals of Nerve Cells." Neuroscience. Sinauer Associates, Inc:
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12. Kohara N, Lin TS, Fukudome T, Kimura J, Sakamoto T, et al. (2002). "Pathophysiology of weakness in a patient
with congenital end-plate acetylcholinesterase deficiency". Muscle & Nerve. 25 (4): 585–592.
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pubmed/11932977).
13. Zalewska E, Hausmanowa-Petrusewicz I, Stahlberg E (2004). "Modeling studies on irregular motor unit
potentials". Clinical Neurophysiology. 115 (3): 543–556. doi:10.1016/j.clinph.2003.10.031 (https://doi.org/10.101
6%2Fj.clinph.2003.10.031). PMID 15036049 (https://www.ncbi.nlm.nih.gov/pubmed/15036049).

External links
Muscles (https://web.archive.org/web/20151107043159/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/
M/Muscles.html)
Muscle and the neuromuscular (http://www.bio.fsu.edu/easton/topic32.html)

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