07-mn neuromuscular junction (1)
TRANSCRIPT
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AnteriorHorn Cells
( Motor
Neurons ).
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Motor Unit: is the
motor
neuron
(Anteriorhorn Cell)
and all the
muscle
fibers it
supplies
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Neuromuscular Junction (NMJ)
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The Neuromuscular junction consists of
A/ Axon Terminal : contains
around 300,000 vesicles whichcontain the neurotransmitter
acetylcholine (Ach).
B/ Synaptic Cleft :20 30 nm ( nanometer ) space
between the axon terminal & themuscle cell membrane. It contains
the enzyme cholinesterase which
can destroy Ach .C/ Synaptic Gutter ( Synaptic
Trough)
It is the muscle cell membrane
which is in contact with the
nerve terminal . It has many foldscalled Subneural Clefts , whichgreatly increase the surface area ,
allowing for accomodation of largenumbers of Ach receptors . Ach
receptors are located here .
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The Neuromuscular junction consists of
The entire structure of axonterminal , synaptic cleft andsynaptic gutter is called MotorEnd-Plate .
Ach is synthesized locally in thecytoplasm of the nerve terminal, from active acetate(acetylcoenzyme A) andcholine.
Then it is rapidly absorbed intothe synaptic vesicles and
stored there.
The synaptic vesiclesthemselves are made by theGolgi Apparatus in the nervesoma ( cell-body).
Then they are carried byAxoplasmic Transport to thenerve terminal , which containsaround 300,000 vesicles .
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Acetylcholine (1) Ach is synthesized locally in
the cytoplasm of the nerve
terminal , from active acetate(acetylcoenzyme A) andcholine.
Then it is rapidly absorbedinto the synaptic vesicles and
stored there.
The synaptic vesiclesthemselves are made by theGolgi Apparatus in the nervesoma ( cell-body).
Then they are carried byAxoplasmic Transport to thenerve terminal , which
contains around 300,000vesicles .
Each vesicle is then filledwith around 10,000 Achmolecules .
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Acetylcholine (2) When a nerve impulse
reaches the nerve
terminal , it opens calcium
channels
calcium diffuses fromthe ECF int the axon
terminal Ca++ releasesAch from vesicles by aprocess of EXOCYTOSIS
One nerve impulse canrelease 125 Achvesicles.
The quantity of Achreleased by one nerveimpulse is more thanenough to produce oneEnd-Plate Potential .
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Ach combines with its
receptors in the subneural
clefts. This opens sodium
channels & sodium
diffuses into the muscle
causing a local,non-propagated potential
called the End-Plate
Potential (EPP), whosevalue is 50 75 mV.
This EPP triggers a
muscle AP which
spreads down inside the
muscle to make it cntract .
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After ACh acts on the receptors , it is hydrolyzed by theenzyme Acetylcholinesterase (cholinesterase ) intoAcetate & Choline . The Choline is actively reabsorbedinto the nerve terminal to be used again to form ACh.This whole process of Ach release, action & destruction
takes about 5-10 ms .
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Myasthenia Gravis Auto-immune disease
Antibodies against Ach receptors destroy many of thereceptors decreasing the EPP , or even preventing itsformation weakness or paralysis of muscles
( depending on the severity of the disease ) .
patient may die because of paralysis of respiratorymuscles.
Treatment : Anti-cholinestersae drugs . These drugsinactivate the cholinesterase enzyme ( which destroysAch) and thereby allow relatively large amounts of Ach toaccumulate and act on the remaining healthy receptors good EPP is formed muscle contraction .
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Drugs Acting on the NMJ
Drugs that stimulate the muscle cell by Acetylcholine-like
action : nicotine , methacholine , carbachol . Drugs that block neuromuscular transmission : Curare and
curare-like drugs ( curariform drugs ) . They have achemical structure similar to ACh , but can not stimulate thereceptors . They occupy acetylcholine receptors and
thereby prevent ACh from acting on its receptors muscleweakness or paralysis . Example : Tubocurarine. It is usedduring some surgical operations .
Anticholinesterase drugs ( e.g. Neostigmine,Physostigmine)Used in treatment of Myasthenia Gravis . These drugs
inactivate the cholinesterase enzyme ( which destroys Ach)and thereby allow relatively large amounts of Ach toaccumulate and act on the remaining healthy receptors good EPP is formed muscle contraction .
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Muscle Physiology
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The Muscle Action Potential
Muscle RMP = -90 mV ( same as in nerves ) .
Duration of AP = 1-5 ms ( longer duration than
nerve AP , which is usually about 1 ms ) .
CV = 3-5 m/s ( slower than big nerves ) .
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Muscle Contraction
There are 4 important muscle proteins :
A/ two contractile proteins that slide upon
each other during contraction:
(1) Actin
(2) Myosin ,
B/ And two regulatory proteins :
(1) Troponin
excitatory to contraction(2) Tropomyosin inhibitory to contraction
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Each muscle cell (fiber) is 10 -80
micrometer long & is covered by a cell-membrane called Sarcolemma.
Each cell contains between a few
hundreds to a few thousands Myofibrils.
Each Myofibril contains 3000 Actin
filaments & 1500 Myosin filaments .
Each myofibril is striated: consisting of
dark bands (called A-bands) and
light (I-bands).
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Muscle Structure (2)
A-bands consist mainly ofMyosin & Actin ; while
I-bands consist of Actin.
The ends of Actin areattached byZ-Discs(Z-lines ).
The part of the Myofibril lying
between two Z-discs is calledSarcomere . It is about 2mcrometers .
When contraction takesplace Actin & Myosin slide
upon each other , & thedistance between two z-discsdecreases : This is calledSliding Filament Mechanism
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Sliding Filament Mechanism: will be discussed later )
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Actin Filament consists of Globular G-actin molecules that are attached
together to form a chain.Each two chains wind togetherlike a double helix
Two F-Actin strands
Groove between the 2 F-
actin strands
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> Each G-Actin molecule has a binding site for Myosin head( called actin active sites )> These active sites are covered and hidden from the Myosin head by
the inhibitory protein Tropomyosin> When Troponin is activated by Ca++ it will move the Tropomyosinaway from these sites and expose them for Myosin.> then myosin immediately gets attached to them .
> when the myosin head attaches to actin it forms a cross-bridge
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The diagram of Guyton
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Myosin (1)
Each Myosin molecule has (1) Head (2) Hinge (joint )
and ( 3 ) Tail ; and each myosin head contains an ATP
binding site as well as ATP-ase enzyme .
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Myosin (2)
Each 200 myosin molecules aggregate to form a
myosin filament , from the sides of which project
myosin heads in all directions .
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The EPP at the motorend-plate triggers a
muscle AP
The muscle AP spreadsdown inside the musclethrough the Transverse
Tubules ( T-tubules )
to reach the Sarcoplasmic
Reticulum (SR) . In the SR the muscle APopens calcium channels
( in the walls of the SR) calcium passively flows
out ( by concentrationgradient ) of the SR into
muscle cytoplasm Ca++combines with Troponin
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The activated troponin pulls the inhibitory protein
tropomyosin away from the myosin binding sites on
actin
and once these sites on Actin are exposed myosin heads quickly bind to them
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This binding activates the enzyme ATPase in the Myosin
Head it breaks down ATP releasing energy which is usedin the Power Stroke to move the myosin head
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The power stroke means tilting of the cross-bridge head (
myosin head ) and dragging ( pulling ) of actin filament
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Then , on order to release the head of Myosin
from Actin , a new ATP is needed to come and
combine with the head of Myosin .
Q: What is Rigor Mortis ?
Q: ATP is neede for 3 things : what are they ?
Q: Is muscle relaxation a passive or activeprocess ? Why ?
Q: What happens to A-band and I-band during
contraction ?
Q: Ca++ is needed in nerve & muscle : when
and where ?
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Summary (1)
(1) Muscle AP spreads through T-tubules
(2) it reaches the sarcoplasmic reticulum where opensits Ca++ channels calcium diffuses out of thesarcoplasmic reticulum into the cytoplasm increasedCa++ concentration in the myofibrillar fluid .
(3) Ca++ combines with Troponin , activating it
(4) Troponin pulls away Tropomyosin(5) This uncovers the active sites in Actin for Myosin
(6) Myosin combines with these sites
(7) This causes breakdown of ATP and release of snergywhich will be used in Power Stroke
(8) Myosin and Actin slide upon each other contraction
(9) A new ATP comes and combines with the Myosinhead .This causes detachment of Myosin from Actin .
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Summary (2)
ATP is needed for 3 things :
(1) Power stroke .
(2) Detachment of myosin from actinactive sites .
(3) Pumping C++ back into the
Sarcoplasmic reticulum .
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Cardiac Muscle (1)
Cardiac muscle is a type of highly oxidative (usingmolecular oxygen to generate energy ) involuntarystriated muscle found in the walls of the heart,
Cardiac muscle is adapted to be highly resistant to
fatigue: it has a large number of mitochondria,enabling continuous aerobic respiration via oxidativephosphorylation,
Role of calcium in contraction In contrast to skeletal muscle, cardiac muscle
requires both extracellular calcium and sodium ionsfor contraction to occur.
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Cardiac Muscle (2)
Like skeletal muscle, the depolarization phaseof the ventricular muscle action potential isdue to entry of sodium ions across into thecell .
However, an inward flux ( influx ) of
extracellular calcium ions through calciumchannels sustains the depolarization ofcardiac muscle cells for a longer duration ,resulting in a plateau Phase that is notpresent in the case of the skeletal muscle AP
Therefore , the cardiac muscle AP lasts for along period ( 200-2300 ms ) and covers mostof the contraction phase . That is why cardiacmuscle can not be tetanized .
Repolarization in the AP , like skeletal muscle ,
is due to potassium efflux .
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Phases of the Cardiac Muscle AP (1)
Phase 4
Phase 4 is the RestingMembrane Potential .
The normal resting membranepotential in the ventricular
myocardium is about -85 to -95mV. This is the period that the cell
remains in until it is stimulatedby an external electricalstimulus (typically an adjacentcell).
This phase of the actionpotential is associated withdiastole ( relaxation ) of thechamber of the heart
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Phases of the Cardiac Muscle AP (2)
Phase 0:
Phase 0is the rapid
depolarization
Phase 1:
Phase 1 of the action
potential occurs with
the inactivation of thesodium channels .
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Phases of the Cardiac Muscle AP (3)
Phase 2
Phase 2 is the "plateau"
phase of the cardiac AP
and is due to calciuminflux into the cell .
Phase 3
Phase 3 is the
repolarization phase and
is due to potassium efflux
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Draw the relationshipbetween a cardiac APand cardiac musclecontraction. How doesthis situation compare
to excitationcontraction coupling ofskeletal muscle?
In skeletal muscle, theelectrical event is overbefore the contractionbegins,
but in cardiac muscle,the electrical andmechanical eventsoverlap considerably.
Tetany is not possiblein cardiac musclebecause of theprolonged refractoryperiod.