8/21/2012

MotorEndPlate

MotorEndPlate

MotorEndPlate(MEP):Structure
Fast(ionotropic)chemical
synapseofamotornerveto
askeletalmusclefiber(cell).
Eachaxonhasmany
branches,whichformMEPs
atmultiplelocationsonone
groupofmusclefibers.
Thesarcolemma (plasma
membrane)ofthemuscle
fiberhasmanyinvaginations,
increasingthesurfacearea
availableforreceptors.
Thepresynaptic vesiclesare
clusterednearthe
postsynapticfolds.

MotorEndPlate

NicotinicACh Receptors
ACh releasedfromthemotor
nervebindstonicotinicACh
receptors(nAChRs).
Thesereceptorsalsorespondto
nicotine(whereasothernon
MEPACh receptorsrespondto
muscarine andarecalled
muscarinic).
nAChRs areionotropic channels
specificforcations.Thecurrent
isprimarilyfromNa+ (largest
EMF),butalsoK+.
nAChR activationproducesan
endplatecurrent,whichthen
causesanendplatepotential
(EPP),analogoustoanEPSP.

2012DavidJulian

8/21/2012

MotorEndPlate

EndPlateCurrents
Exocytosis ofeachvesiclereleasesaquantum ofACh,
whichproducesaminiatureendplatecurrent.Thisis
insufficienttogenerateanAPinthemusclefiber.
AsinglemotorneuronAPreleasesatleast100quanta
(vesicles)ofACh,whichissufficienttoinitiateanAPin
themuscle.

MotorEndPlate

NicotinicACh ReceptorCurrent
Thetotalendplatecurrent(IEP)isdeterminedbythe
numberofavailablechannels(n),theopenprobability
ofeachreceptor/channel(po),thesinglechannel
conductance(),andthetotalEMF(forNa+ andK+):

IEP =n po (Em ENa,K)

Theopenprobabilityofeachreceptorisdependenton
theamountofACh presentinthesynapticcleft.

MotorEndPlate

InitiationofaMuscleFiberAP
Theendplatecurrentisverylargecomparedtothatofa
typicalneuronneuronsynapse,andthereforetheEPPis
alsoverylarge(~70mV)comparedtoanerveEPSP.
VoltagegatedNa+ channelsinthesarcolemma willbecome
activatedbytheEPP,initiatinganallornoneAPinthe
musclefiber,whichthenpropagatesacrossthesarcolemma
viavoltagegatedNa+ channels.
Althougheachmyocyte isonlyinnervatedbyonemotor
nerve,theremaybemultiplesynapsesfromthatnerveon
thefiber(fromcollateralbranches).Thisallowsmore
synchronousdepolarizationofamusclemyocyte (which
canbe15cmlonginhumans).

2012DavidJulian

8/21/2012

MotorEndPlate

ACh DeactivationandCholine Reuptake

Acetylcholinesterase (AChE)rapidlydegradesACh in
thesynapticcleft.Subsequentreuptakeofcholine by
thepresynaptic terminalallowssomerecycling.
ManyinsecticidesareAChE inhibitors.

Muscle

Muscle

OverviewofMuscleTypes

2012DavidJulian

8/21/2012

SkeletalMuscleStructure

SkeletalMuscleStructure

HierarchicalOrganizationofSkeletalMuscle
Musclesareattachedatendstobone
orotherstructuresviatendon.
Amuscleismadefrommany
myofibers arrangedinparallel.
Eachmyofiber isalong,cylindrical,
multinucleatecell(formedbyfusion
duringemryogenesis)thatconsistsof
manyparallelmyofibrilsubunits.
Eachmyofibriliscomposedof
repeated,2m,sarcomere subunits.
Thesarcomere isthefunctionalunit
thatshortensduringcontraction.

SkeletalMuscleStructure

Sarcomere Structure
Asarcomere iscomposedofthreemainfilaments:
1. Actin ("thin")filaments.About2000persarcomere.Attachedat
midpointtoZdisksandprojecttoeitherside.
2. Myosin("thick")filaments.About1000persarcomere.Atthecenter
ofeachsarcomere andattachoneachendtoactin filamentsfrom
oppositeendsofthesarcomere.
3. Titin (orconnectin)filaments.10%oftotalmusclemass.Functionas
elasticbands.Longestknownpolypeptide(30,000aminoacids).

2012DavidJulian

8/21/2012

SkeletalMuscleStructure

Actin Filament
Eachactin filamentiscomposedof:
A. Two"twisted,beaded"polymerchainsof~400globular
actin molecules.
B. Twostrandsoftropomyosin moleculesthatlieendtoend
inthegroovesformedbytheactin chains.
C. Troponin (TN)molecules,attachedatintervalstothe
tropomysin strands.EachTNconsistsofthreesubunits:
1. TNC tworegulatorybindingsitesforCa2+
2. TNI inhibitsslidingoffilamentsatrest
3. TNT bindsTNcomplextotropomyosin.

SkeletalMuscleStructure

MyosinFilament
Eachmyosinfilamenthas
ca.300myosinII
moleculesarrangedin
helicalpairs.
EachmyosinIIhasa
globularheadwithan
actinbindingdomain
(actinattachmentsite),a
nucleotidepocket(ATP
hydrolysissite),anda
flexibleneckwithtwo
"lightchains".
Theleverarmsegment
tiltstoasmallerangle
whenthemolecule
interactswithactin.

SkeletalMuscleStructure

TTubulesandSR
Thesarcolemma formsdeep,"Tshaped,transverseinvaginations
intothemyocyte,calledtransversetubules orTtubules.
ThelumenoftheTtubulesystemiscontinuouswiththeECF(and
thereforehas1000xhigher[Ca2+]thanthesarcoplasm).
AsanAPpropagatesalongthesarcolemma fromtheMEP,it
continuesintotheTtubules.Therefore,theTtubulesystem
spreadsanAPdeepintothemyocyte.

2012DavidJulian

8/21/2012

ExcitationContractionCoupling

ExcitationContractionCoupling

TriadsandCalciumRelease
TheSRexistsinlongitudinal
tubulesbetweentheT
tubules.Thejunctionoftwo
SRtubuleswithaTtubuleis
calleda"triad".
Atthetriad,theSRcontains
avoltagesensitiveCa2+
channelsystem(described
onnextslide).
Ttubuledepolarization
activatesthissystem,which
releasesCa2+ fromtheSR
intothesarcoplasm.
Increased[Ca2+]i isfollowed
bycontractionofthe
sarcomeres.

ExcitationContractionCoupling

SkeletalMuscleRYR1andDHPR
Inskeletalmuscletriads,theSRcontainsaCa2+ channelcalleda
ryanodine receptor(RYR),andtheTtubulecontainsareceptor
calledthedihydropyridine receptor(DHPR).
Inskeletalmuscle,RYR("RYR1")andDHPRformacomplexat
thetriad.DHPRis"activated"byTtubuledepolarization,and
theactivatedDHPRthendirectlystimulatesRYRtoopen.Note
thatDHPRisnot achannel.
Therefore,depolarizationoftheTtubulecausesCa2+ efflux
fromtheSRintothesarcoplasm.

2012DavidJulian

8/21/2012

ExcitationContractionCoupling

CardiacMuscleRYR2andDHPR
Incardiacmuscle,DHPRisbothareceptorand aCa2+
channel.
DHPRisactivatedbyTtubuledepolarization,allowingCa2+
toenterthesarcoplasm fromtheTtubule.
TheCa2+ thenstimulatescardiacmuscleRYR("RYR2")to
open.ThisisknownasCa2+stimulatedCa2+ release.

ExcitationContractionCoupling

SlidingFilaments
Atrest,themyosinheadisat90 andhasATPinitsnucleotidebindingsite,
buttropomyosin "covers"thesiteonactin atwhichmyosinwouldbind.
1. BindingPhase:WhenCa2+ risesabove1M,itbindstotroponin (TNC),
whichmovestropomyosin,allowingmyosinactinbinding.Thispermits
myosinATPase activity,hydrolyzingATPtoADP+Pi (Pi remainsattached).
2. WorkPhase(10%ofcycletime):MyosinreleasesPi,flexingthemyosin
headby40 (to50),slidingmyosinalongactinintheprocess.ADP
releasethencauses5 moreflexion(to45).
3. RestingPhase(90%ofcycletime):ADPisreplacedwithATP(ifpresent),
thenmyosinreleasesfromactin andunflexes.

ExcitationContractionCoupling

ContractionCycle
Ca2+ iscontinuouslypumpedback
intotheSR.
However,withcontinuedAPs,
[Ca2+]i remainshigh,andinthe
presenceofATP,thecontraction
cyclewillcontinuetorepeat,
causingprogressiveshorteningof
thesarcomeres (ormaintenanceof
tension).
Thedimer arrangementofmyosin
letsoneheadreleasewhilethe
otherstaysbound,allowingtension
tobemaintained.
IntheabsenceofATP,themuscle
formsastablerigorcomplex.

2012DavidJulian

8/21/2012

ExcitationContractionCoupling

MotorUnits
Asinglemotorneuronhasoneaxonthatsplitsintomany
collaterals,eachofwhichcanhavemanybranches,with
eachterminatinginamotorendplate.
Eachmotornervestimulatesuptothousandsofindividual
musclefibers(cells),buteachmusclecellisonlyinnervated
byonemotornerve(someinvertebrateshaveboth
excitatoryandinhibitorynervescontrollingamusclefiber).
Onemotorneurontogetherwithalltheskeletalmuscle
fibersitinnervatesisamotorunit.Therefore,whena
motornervedepolarizes,allofthemusclecellsinthat
motorunitwillcontracttogether.

ExcitationContractionCoupling

GradedMuscleActivity
Inskeletalmuscle,eachAPofeverymyocyte inamotorunit
causesanallornonetwitch.Stronger(graded)contractions
areachievedbytwomechanisms:
1. Recruitmentofmotorunits increasingthenumberof
motorunitsthatarestimulatedatthesametime.Notethat
althoughrecruitmentincreasestheforceofacontraction,it
decreasesthefinemotorcontrol
2. IncreasedfrequencyofneuronalAPs morefrequentAPs
causesustainedelevationofintracellularCa2+,whichallows
continuedformationofcrossbridgesandgreatershortening
ofsarcomeres.

MechanicsofMuscle

2012DavidJulian

8/21/2012

MechanicsofMuscle

TypesofSkeletalMuscleContraction
Twitch:singleallornonecontraction.
Mechanicalsummation:repetitivestimulationcausesindividual
twitchestofuse,increasingsarcomere shorteningandcontraction
force.
Tetanus:summationsorapidthatnorelaxationispossiblebetween
twitches.Achievesmaximumforce.
Contracture(spasmorcramp):causedbypersistentlocal
depolarization(i.e.,notcausedbymotornerveAPs).Forexample,
fromincreasedextracellularK+ ordruginducedCa2+ release(asfrom
caffeine).
Isometric:increasedforce,constantlength.
Isotonic:decreasedlength,constantforce.

MechanicsofMuscle

IsometricForceandSarcomere Length
Musclegenerates
maximumforceata
degreeofstretchthat
producesmaximal
actinmyosinbridges
(~2.2m).
Toomuchstretch
preventssomecross
bridgesfromforming.
Toolittlestretch
allowssteric
hindrance(crowding)
ofcrossbridges.

MechanicsofMuscle

ActiveandPassiveMuscleForce
Totalmuscleforceisthesumofactiveforce(dueto
contraction)andpassive"extension"force(duetoelastic
elements;primarilytitin).
Maximumactiveforceisproportionaltomusclecross
sectionalarea,whereascapacitytodoworkisdependenton
musclemass(i.e.,bothareaandlength).

2012DavidJulian

8/21/2012

MechanicsofMuscle

NormalWorkingRange
Skeletalmuscleis"prestretched"(bybonesandtendons)at
theoptimallengthtoproducemaximalforceatthe
beginningofacontraction.
Cardiacmuscleistypicallystretchedtolessthanoptimal
whentheheartisfilledwitharestingvolumeofblood.This
allowsincreasedfilling(e.g.,duringexercise)togenerate
increasedforcewith(moreaboutthislater).

End

2012DavidJulian

10