07-MN Neuromuscular Junction (1)

8/8/2019 07-MN Neuromuscular Junction (1)

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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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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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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.

07-MN Neuromuscular Junction (1)

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