Neuro Muscular Transmission

8/13/2019 Neuro Muscular Transmission

1/14

Neuromuscular Transmission

Case 1: A 64 year old male was brought to the emergency room of a small rural hospital by his

wife. She explained that her husband complained of dryness of the mouth and nausea followed

by severe vomiting about 1 hours after consuming green beans from a !ar that she had preservedthe previous fall. "n the emergency room# the patient displayed blurred vision# partial paralysis of

respiratory muscles and proximal muscles of the limbs. $e was placed immediately on a

respirator and given iv antitoxin. %he patient was given an enema and cathartic to eliminatepossible bacteria and toxin remaining in the &" tract. Culture of the remaining contents of the !ar

revealed Chlostridium botulinum.

Case : A '' year old female came to her physician with a chief complaint of muscle wea(ness.

She states that the wea(ness worsens with exercise and improves with rest. )pon referral to a

neurologist# an electromyographic *+,&- test was done. %he +,& revealed a normal response

to stimulation of the nerve or muscle separately. A single stimulus of the nerve resulted in a

normal muscle contraction. $owever# with repetitive stimulation of the nerve# muscle contractionbegan to fail# and a smaller muscle +,& was seen. %he patient was diagnosed with ,yasthenia

&ravis# confirmed with a test dose of an anticholinesterase drug called physostigmine. %wo drugtherapies were ordered. /irst# she was placed on an anticholinesterase drug. Second# she was

placed on immunosuppressive therapy. "n addition she was referred to a surgeon for possible

removal of her thymus gland.

%he two cases outlined above define the pathophysiology of neuromuscular transmission. %he

first case loo(s at a problem involving transmitter release from the motor nerve terminal. %he

second describes the clinical syndrome associated with loss of acetylcholine receptors located atthe muscle endplate.

A Synapse is a contact between a nerve and another nerve# muscle or gland cell. ,ostsynapses are Chemical in which a chemical transmitter conveys information from presynaptic to

postsynaptic cell. A small number of synapses are +lectrical in which a low resistance electrical

contact transmits information from presynaptic to postsynaptic cell. %he neuromuscular!unction is the classic chemical synapse.

A) Overview of Neuromuscular Transmission

An action potential originating at the axon hilloc( of a motor neuron is conducted to the

nerve terminal0

erve terminal is depolari2ed opening Ca channels

03esicles fuse with nerve terminal membrane and release Acetylcholine *Ach-

0

ACh binds to receptors on the muscle endplate 5epolari2ation of the musclemembrane

1


2/14

0

%hreshold of 3oltagesensitive a channels in muscle membrane is reached# and muscleA fires

0

A spreads over surface of muscle and muscle contracts

B) Structure of the Neuromuscular Junction

1- At the neuromuscular !unction an alpha motor neuron loses its myelin sheath andforms numerous nerve terminal branches. +ach of these branches ends in a

terminal bulb called a 7bouton.8

- %he terminal boutons remain close and form synaptic contacts on a speciali2ed

area of muscle cell membrane called the 7endplate.8

'- 9etween the 7presynaptic8 nerve terminal and the 7postsynaptic8 muscle end

plate is nm cleft containing a basal lamina sheath consisting of collagen andextracellular matrix proteins. An en2yme 7acetyl cholinesterase8 is also present in

the synaptic cleft. %his en2yme hydroly2es Acetylcholine into choline plus

acetate.


3/14

4- Structures in the erve %erminal

a- All nerve terminals in chemical synapses contain: vesicles with

transmitter# mitochondria and an 7active 2one8 where vesicles bind andrelease their contents into the synaptic cleft

b- erve terminals also contain Ca channels near the active 2ones. Ca

facilitates the fusion of vesicles with the nerve terminal membrane. "nthe absence of Ca# neuromuscular transmission cannot occur.

;- Structures in the Synaptic Cleft

a- %he nm cleft is filled with collagen and extracellular matrix proteins.

Acetylcholine esterase *ACh+- is also located in the cleft attached to the

collagen.b- 5uring development molecules are expressed that enable the growing

nerve terminal to form a synapse on the correct target.

c- to diffuse down their

'


4/14

chemical gradients. %hus a moves in and ? moves out leading to a

depolari2ation of the endplate membrane.

d- 3oltagesensitive a channels are located at the bottoms of the folds andin all the rest of the muscle membrane. "f the endplate depolari2ation is

sufficient to reach threshold# a muscle A will fire# and the muscle will

contract.

C) Steps in Neuromuscular Transmission Pre-synaptic

1- erve %erminal Action otential @pens Ca Channels

a- 3oltagesensitive Ca channels are especially concentrated in nerve

terminal endings near vesicle release sites. %hese Ca channels haveactivation and inactivation gates# but are slow to open and close.

b- 9ecause they are slow# the Ca channels open during the falling phase of

the nerve terminal A. %he Ca channels are open long enough to allow

a rise in intracellular Ca of 1 times normal * 1

4

,# whereas normalis 1B,-.

c- %he rise in Ca>> near vesicle binding sites allows fusion of vesiclemembranes with the nerve terminal membrane.

d- 3esicle 5oc(ing A fusion pore develops beneath a 7doc(ed8 vesicle.

A channel forms through the fusion pore allowing some ACh to be

released. "n the final state an 7omega figure8 is formed# and the ACh isreleased from the vesicle. %he vesicle membrane becomes incorporated

into the nerve terminal membrane.

4


5/14

e- 3esicle Decycling

*1- Slow to ,oderate rates of stimulation 7?iss and Dun 5oc(ing.8

*- /ast Stimulation /usion and Decycling of ,embrane.

a- 3esicles fuse with nerve terminal membrane# form @mega

figures# and combine with the membrane

b- Clathrin forms around an invaginated region of membrane.Clathrin proteins form a bas(et around a pinched off piece

of nerve terminal membrane# and transport it to the

endosome.

c- ew vesicles are formed from the endosome and move tothe terminal along cytos(eletal elements.

d- ewly formed vesicles are refilled with ACh by the

reaction of choline > acetate cataly2ed by the en2ymeAcetylcholine transferase.

;


6/14

f-


7/14

*;- Step ;:


8/14

/igure Above. @n the left are /ree2efracture electron micrographs# before *above- and during

*below- stimulation and vesicle fusion. @n the right are traditional electron micrographs ta(enduring approximately the same time periods for orientation. */rom ?andel# Jessell and

Schwart2-.

) Steps in Neuromuscular Transmission Post Synaptic

1- Acetylcholine is released into the synaptic cleft directly opposite the ACh

Deceptors. %hese are 7nicotinic8 acetylcholine receptors because they have a high

affinity for nicotine as apposed to 7muscarine8 typical of the autonomic nervoussystem.

- ,ost acetylcholine never reaches the Ach receptors. %hat is because the synaptic

cleft is filled with the en2yme acetylcholine esterase *ACh+- that hydroly2es mostof the Ach. %he released Ach must pass through this en2yme 7gauntlet.8

Ach > Ach esterase acetate > choline

'- %he choline is ta(en bac( into the nerve terminal where it is combined withAcetyl CoA in the presence of the en2yme CA% *choline acetyl transferase-. %he

Ach is then repac(aged in vesicles for future release.

K


9/14

Choline > AcetylCoA > CA% Acetylcholine

4- and ?>.

;- %he opening of the Achcontrolled channel leads to a depolari2ation of the end

plate region called the 7endplate potential.8

6- %he + is recorded by placing a microelectrode into the muscle cell near the

endplate.

a- A typical + is about ;6 m3 in amplitude. "t is usually not seen

because as the muscle membrane is depolari2ed to threshold# voltagesensitive a channels on the muscle membrane are activated leading to

an allornone Action otential.

b- 9ut it is possible to reduce the amplitude of the + to below thresholdusing curare# a South American al(aloid used by natives for arrow

poison.

L


10/14

c- Curare binds to the ACh receptor# and competes with ACh. Although

curare binds to Ach receptors# it cannot open the receptor channel# and

thus cannot depolari2e the endplate membrane. %herefore# the ACh

released from vesicles produces less depolari2ation of the endplatemembrane.

d- Curare was used in the past as an agent for muscle paralysis to permit

surgery especially around !oints. "t has since been replaced by fasteracting and more controllable agents.

e- /or our purposes here# use of curare shows the form of the +.

B- %he + is made up of the synchronous release of the contents of about 11;

pac(ets *vesicles- of ACh# each pac(et causing a small depolari2ation of about

.; m3

1


11/14

a- "n 1L; aul /att and 9ernard ?at2 placed a microelectrode in a

neuromuscular !unction# and watched what happened in the absence of

stimulation

b- %hey observed spontaneous small potentials *.; m3 in mammals-

occurring randomly at about 1=sec. 9ecause these small depolari2ationscould only be recorded at the endplate# they were called 7,iniature

endplate potentials8 *,+s-.

c- +ach ,+ is thought to represent the spontaneous release of the

contents of one synaptic vesicle# and thus is called a 7Iuantum of

transmitter release.8

d- Stimulation of the motor nerve causes the opening of Ca channels. Ca

influx causes the spontaneous release rate to increase by a factor of

1# times# but it only lasts about 1.; msec. %his computes to about

1; pac(ets of ACh released per impulse.

K- Characteri2ation of the Acetylcholine Deceptor

1- ?arlin and Changeux are primarily responsible for our understanding of thestructure and function of the nicotinic ACh receptor *AChD-.

- %he icotinic AChD consists of five subunits: two MNs# O# P and Q. /or

maximum effect two ACh molecules must bind to the receptor# one at each

alpha site.'- @nce ACh is bound the channel opens# and a> flow into the cell down its

electrical and chemical gradientR ?> flows out down its chemical gradient.

9ernard ?at2 termed this 7a chemical puncture8 of the endplate membrane.

11


12/14

4- and ?> simultaneously cause

endplate depolari2ationE Consider each ion independently:

a- Suppose the endplate membrane were 7punctured8 only for a>. %hat

is what happens during the rising phase of the Action otential. "n other

words# the membrane potential is driven toward the aeIuilibriumpotential *+a> >66 m3-.

b- ow consider what would happen if the endplate membrane were7punctured8 only for ?>. "n this case the membrane potential would be

driven toward the eIuilibrium potential for ?> *L; m3-.

c- Consider now what would happen if you punctured the endplatemembrane for both ions at the same time. %he membrane potential

would be driven to a point somewhere between the two eIuilibrium

potentials. "n fact# it is driven to 7 m3.8 %his is called the eIuilibrium

potential for the + *++ m3-.

d- %his eIuilibrium potential for the + is sometimes called the 7reversal

potential.8 %hat means that if you artificially 7clamped8 or set the end

plate membrane at m3# a> influx would balance ?> efflux. "f youstimulated the nerve and ACh were released# the amplitude of the +

would be m3. "f you artificially clamped the endplate membrane at#

say >1 m3# the + would actually be upsidedown# or 7reversed.8e-


13/14

f- +ven though the Ach channel when opened is eIually permeable to both

a and ?# most of the current is carrie! "y Na#66-# there is a greater drivingforce for sodium than for potassium.

;- $ow does the + lead to a ,uscle Action otentialE

a- %he endplate is usually found in the center of a muscle fiber.

b- Decall the discussion about conduction of a nerve action potential.5epolari2ation of the endplate membrane causes a discharge of

the capacitance in the surrounding muscle membrane. +ventually

enough charge is drawn off of this capacitance to bring themuscle membrane to 6 m3# the threshold for voltage sensitive

achannels.

c- %he voltagesensitive a channels are located in the depths of the endplate folds and in the muscle membrane away from

the endplate.

d- As these voltagegated a channels reach threshold# the

activation gates open and *!ust as in nerve axons- a regenerative

muscle action potential occurs.

e- %he A is conducted from the center of the muscle fiber outward.

%his eventually leads to muscle contraction *discussed later -.

6- Desolution of Case H:

1'


14/14

a- ,yasthenia &ravis degeneration of endplate ACh Deceptors. %his

is an autoimmune disease in which nicotinic Ach receptors are downregulated and

degenerate# resulting in neuromuscular bloc(. "t is treated by an immunosuppressantand anticholinesterase therapy.

tosis in a patient with ,yasthenia &ravis. Above# patient could not move his eyes

to loo( to either side# and his eyelids drooped. 9elow# one minute after i.v.

in!ection of edrophonium chloride *an ACh+ inhibitor-# the patient could raise his

eyelids and move eyes from side to side. */rom ?andel et al# rinciples of euralScience# /ourth +dition.-

b- Anticholinesterase treatment is effective because

bloc(ing this en2yme allows more Acetylcholine to reach the few

receptors that are remaining. )sually this is sufficient to depolari2e

the muscle endplate membrane to threshold and muscle

contraction will occur.

14

Neuro Muscular Transmission

Documents

Transcript of Neuro Muscular Transmission