SignalTransductionPathways

• Ifithelps,thinkofsignaltransductionpathwayslikewhathappenswhenyougetatextmessage:– Reception =Yourphonevibratesordings.– Transduction =Youunlockthephoneandreadthemessage.

– Response =Youwriteback,smile,cry,orlaugh.

TheSignalTransductionPathwayThreeSteps

• Step1:Reception– Thecellneedstoreceiveachemicalsignal(aligand).• Aligandisanysmallmoleculethatbindstoalargerone.• Thelargermoleculeisusuallyareceptorprotein.

TheSignalTransductionPathwayThreeSteps

• Step2:Transduction– Themembranereceptorproteinthenactivatesoneormoreothermoleculestocarrythesignaldeeperintothecell.

– Theseothermoleculesarecalledrelaymolecules andmaybeinvolvedinaphosphorylationcascade.

TheSignalTransductionPathwayThreeSteps

• Step3:Response– Thecelldoessomething.– Thiscouldbetheactivationofagene,changeinthecytoskeleton,activityofanenzyme,orjustaboutanythingelse.

KinaseAction

PhosphorylationCascade

TimetoPractice

• SignalTransductionPathwaysPOGIL

ExamplesofSignalTransductionPathways

• Asignaltransductionpathwaycanbe“achieved”throughoneofthesefourtotalmethods:– IntracellularReceptors– Extracellular(CellSurfaceTransmembrane)Receptors1. GProtein-CoupledReceptors2. Tyrosine-KinaseReceptors3. IonChannelReceptors

IntracellularReceptors

• Thisiswhenasignalmolecule,stillcalledaligand,enters acelltoelicitaresponse.

• Insidethecell,itbindstoareceptorproteininthecytoplasmandthencanaffecttranscriptionorothercellactivities.– Inthiscase,wecouldcalltheligand/receptorcomplexatranscriptionfactor.

• Ontotheextracellular receptors!

1.GProtein-CoupledReceptor• Gproteinsareguaninenucleotide-bindingproteins.

• So,aGprotein-coupledreceptor(GPCR)isamembranereceptorthatislinkedinsomewaytoaGprotein.– There’stheGproteinandthere’sthereceptor(they’redifferent).

• Gprotein-linked receptorshavesevenαhelicesspanningthemembrane.

• Thesereceptorsareresponsibleforrelayingasignalfromaligandtotheinteriorofthecell(NOTrelayingtheliganditself).

EnergyMolecules• BeforewelaunchintohowaGprotein-coupledreceptorworks,weneedtolookintoamoleculethatpowerstheGprotein.

• WhatamItalkingabout?• No,notATP…GTP!– ATP=Adenosinetriphosphate– GTP=Guanosine triphosphate

• Key:EachisanucleotidewithTHREEphosphategroups.

• Key:When“usedup,”themoleculeisreducedtoTWOphosphategroups,knownasadenosine/guanosine diphosphate.

ATPvs.GTP

• They’resimilar,butdifferentinthesamewaythatadenineandguaninearedifferent.– Adenosine=adenine(anitrogenousbase)+ribose– Guanosine =guanine(anitrogenousbase)+ribose

• ATPisthemorefamiliarenergy“currency”ofthecell,butGTPplaysaroletoo.– Thekeyisnotsomuchthe“adenosine”or“guanosine”partasisthe“triphosphate”part.

– Thebondsbetweenthephosphategroupscontaintheenergy.

BacktoGProtein-CoupledReceptors• Inactive:– Thereceptorisspanningthemembrane.– TheGproteinisboundtoGDPandstucktotheinnermembrane.– Anenzymealsoexistsontheinnersurfaceofthecellmembrane.

BacktoGProtein-CoupledReceptors• Activation:– TheorangeligandactivatestheGPCR,changingitstertiarystructure,whichbondstotheGprotein.

– GTPreplacesGDP,andtheGproteinmovestotheenzyme.– Theenzymepromptsthenextcellularresponses.

BacktoGProtein-CoupledReceptors

• Deactivation:– TheenzymehydrolyzesGTPandremovesaphosphate.– TheGproteinisreleased.Theprocesscanstartagain.

AndIcare…because?

• SowhyareGprotein-coupledreceptorsimportant?– YourvisionandsmellsensesuseGprotein-coupledreceptors.

– Diseaseslikebotulism,pertussis(whoopingcough),andcholeraproducetoxinsthatinterferewithGPCRs.

– Around60%ofmedicineworksbyaffectingGPCRs,andawholelotofdrugs(includingheroin)workthesameway.

– PTCpaper:tasted(ornot)?• YourabilitytotastePTCisbasedonwhetheryouhaveagenecodingforaGprotein-coupledreceptorforthatsubstance.

• NoGPCR,noPTCtaste.

2.Tyrosine-KinaseReceptors

• Tyrosine-kinaseisanenzymestuckinthecellmembrane.

• ItsjobistodephosphorylateATPandmovethatphosphategrouptotheattachedtyrosine.

• IthasabindingsiteintheECMforsignalmoleculesandsingleαhelixinthemembrane.

Tyrosine-KinaseReceptors• Inactive– Thetyrosine-kinasereceptorproteinsaretwoseparatemonomers,andrelayproteinsarenotactive.• Takeaguesswherethisisgoing…

Tyrosine-KinaseReceptors• Activated– Aligandactivatesthemonomersandtheymakeadimer.– Oncejoined,thekinasedephosphorylatesATPandaddsthatphosphategrouptoitstyrosine(aminoacid),whichactivatesrelayproteins.

Tyrosine-Kinasevs.GProtein

• GproteinstendtoelicitonlyonetypeofresponseperGprotein.

• Asingletyrosine-kinasereceptorcancausemultipleresponses.– Errantreceptortyrosine-kinaseshavebeenlinkedtocancer.

3.IonChannelReceptors

• Theseareproteinchannelsthatopenonlywhenactivatedbyaligand.

• Nervecellsusethesefrequently.

Receptors:BigIdeas• Versatility:Differentcelltypescanrespondtothesameligandindifferentways:

Receptors:BigIdeas• Scaffolding:Someproteinsserveasintermediatesandholdrelayproteinstogether.

Receptors:BigIdeas• Amplification:Asinglesignalmoleculecanleadtoamassiveresponse.– Thisisthepointofaphosphorylationcascade.

SecondMessengers

• Signaltransductionpathwaysoftenactivatesecondmessengers.– Thesearemoleculeswithin cellsthatactassignalsjustliketheoriginalextracellular signal.

• Thethreemajorclassesofsecondmessengers:– Cyclicnucleotides– DAGandIP3– Calciumions(Ca2+)

SecondMessenger:CyclicNucleotides

• Theenzymeadenylylcyclase isactivatedbyaGprotein.– Adenylylcyclase usesATPtomakecAMP,orcyclicAMP.

– AMP=adenosinemonophosphate• Similarly,guanylyl cyclase usesGTPtomakecGMP (cyclicGMP).

• Thesesecondmessengersthenservetoturnonotherresponseswithincells.

SecondMessenger:IP3 andDAG

• DAGisdiacylglycerol whichstaysinthecellmembraneandactivatesotherenzymes,whichoftenuse…

• …IP3,whichisinositoltriphosphate.– ThishelpsreleaseCa2+ ions(whicharethemselvesconsideredasecondmessenger)fromtheER.

• Calciumions,bytheway,areusedwidelythroughoutthebody.– Includingmakingyourmusclescontract.

AnotherView

Aside:ClownAnemonefish

• You’veseenFindingNemo,right?• Whatthatmoviedidn’ttellyouisthatclownfish(clownanemonefish,officially)haveaninterestingstructureintheirsocialgroups.

• Thereisonlyonefemaleandonereproductivemale.– Allothersaresmallermaleswhosespermisinhibitedbythefemale.Allclownanemonefisharebornmale.

• Whenthefemaledies,thereproductivemalebecomesfemale witharushofestradiolhormone.– Thenextbiggest(notnecessarilyoldest)malebecomesthereproductivemale.

http://2.bp.blogspot.com/-0aMlLqUGGLI/TV9-haWanCI/AAAAAAAAAzk/goTrWowOCZE/s1600/2c64d3bfebwnfish.jpg.jpg

Aside:ClownAnemonefish

• Whatdoesthismean?• Itmeansthat,assumingtherewerenootherindividualsinNemo’s group,afterNemo’s mom’sdeath,Nemo’s dadwillsoonbecomeNemo’s mom.

• Nemo,meanwhile,willbecomereproductiveandmatewithhisfathermother,untilheshe diesandNemo becomesfemale,perhapsmatingwithhisownoffspring.– Doryshouldhavejuststayedaway…

http://2.bp.blogspot.com/-0aMlLqUGGLI/TV9-haWanCI/AAAAAAAAAzk/goTrWowOCZE/s1600/2c64d3bfebwnfish.jpg.jpg

TheCatch:Homeostasis

• Allthissignalingisgreat,butthere’sonemajorcatch:organismsstillneedtomaintainhomeostasis.

• Theycanachievethisthroughfeedbackloops.• Positivefeedback amplifiestheoriginalsignal.• Negativefeedback inhibitstheoriginalsignal.– Asyoumightguess,negativefeedbackisfarmoreusefultohomeostasis.

NegativeFeedbackExamples

• Predator-PreyRelationships– Increaseinpreyleadstoanincreaseinpredators…whichdecreasesprey.

• BodyTemperature– Ariseinbodytemperatureissensedbyneuronswhichsignalthebrain,whichsendssignalstodilatethebloodvessels(vasodilation),decreasingtemperature.• Andmakingyouredintheface.

NegativeFeedbackAnotherExample

• IfthepHintheduodenum(partoftheintestine)dropstoolow…

• …thecellsintheintestinereleasesecretin,achemicalsignal,intotheblood.

• Secretintravelstothepancreas,whichreleasesbicarbonate…

• …whichraisesthepH.

PositiveFeedbackExamples

• Stampedes– Afewanimalsstarttostampede,causingmoretorun,leadingtoamassmovement.

• Uterinecontractions– Oxytocincausesuterinecontractions,whichmovesthefetusfurtherdownthebirthcanal,whichstimulatesmoreoxytocinrelease.

• Studentspackingupattheendofclass?

Awkwardstockphoto fromoldPowerPoint…atwhatexactlyarethey

alllooking?

PositiveFeedbackAnotherExample

• Ifabreakoccursinabloodvessel…

• …plateletsadheretoitandreleasechemicals…

• …whichattractmoreplateletsuntiltheprocessends.

PositiveFeedbackOnelastone…

• Theoceanisamajorcarbonsink.• Carbondioxidedissolvesbestincoldwater.• AsCO2 levelscausetemperaturestorise,moreCO2 precipitatesfromtheocean.

• MoreCO2 comingoutoftheoceanraisestemperatures…

• …whichreleasesmoreCO2.

CouplingFeedbackLoops

• Rememberthatnegativefeedbackloopsarebestforhomeostasis.

• Topreventanylevelorratefromgettingtoohigh,youneedafeedbackloop.

• Topreventanylevelorratefromgettingtoolow,youneedanother feedbackloop.

• Key:Acoupled(ordouble)feedbackloopisneededtokeephomeostasis.– Let’slookatsomeexamples.Knowthekeycomponents.

CalciumHomeostasis

BloodCa2+ high

Calcitoninreleased

BloodCa2+lowered

BloodCa2+ lowBloodCa2+raised

CalciumHomeostasis

ParathyroidHormone(PTH)released

GlucoseHomeostasis

Bloodglucosehigh

Insulinreleased

Bloodglucoselowered

Bloodglucoselow

Bloodglucoseraised

GlucoseHomeostasis

Glucagonreleased

Closure:FeedbackMechanismsPOGIL

• It’stimetoputourknowledgeoffeedbackmechanismstothetestusingaPOGIL.

• FeedbackMechanisms POGIL• Also:– TED:Anje-Margriet Neutel – FeedbackLoops:HowNatureGetsitsRhythms