Signal Transduction Pathways - drgatz.com · Signal Transduction Pathways • If it helps, think of...
Transcript of Signal Transduction Pathways - drgatz.com · Signal Transduction Pathways • If it helps, think of...
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SignalTransductionPathways
• Ifithelps,thinkofsignaltransductionpathwayslikewhathappenswhenyougetatextmessage:– Reception =Yourphonevibratesordings.– Transduction =Youunlockthephoneandreadthemessage.
– Response =Youwriteback,smile,cry,orlaugh.
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TheSignalTransductionPathwayThreeSteps
• Step1:Reception– Thecellneedstoreceiveachemicalsignal(aligand).• Aligandisanysmallmoleculethatbindstoalargerone.• Thelargermoleculeisusuallyareceptorprotein.
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TheSignalTransductionPathwayThreeSteps
• Step2:Transduction– Themembranereceptorproteinthenactivatesoneormoreothermoleculestocarrythesignaldeeperintothecell.
– Theseothermoleculesarecalledrelaymolecules andmaybeinvolvedinaphosphorylationcascade.
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TheSignalTransductionPathwayThreeSteps
• Step3:Response– Thecelldoessomething.– Thiscouldbetheactivationofagene,changeinthecytoskeleton,activityofanenzyme,orjustaboutanythingelse.
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KinaseAction
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PhosphorylationCascade
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TimetoPractice
• SignalTransductionPathwaysPOGIL
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ExamplesofSignalTransductionPathways
• Asignaltransductionpathwaycanbe“achieved”throughoneofthesefourtotalmethods:– IntracellularReceptors– Extracellular(CellSurfaceTransmembrane)Receptors1. GProtein-CoupledReceptors2. Tyrosine-KinaseReceptors3. IonChannelReceptors
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IntracellularReceptors
• Thisiswhenasignalmolecule,stillcalledaligand,enters acelltoelicitaresponse.
• Insidethecell,itbindstoareceptorproteininthecytoplasmandthencanaffecttranscriptionorothercellactivities.– Inthiscase,wecouldcalltheligand/receptorcomplexatranscriptionfactor.
• Ontotheextracellular receptors!
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1.GProtein-CoupledReceptor• Gproteinsareguaninenucleotide-bindingproteins.
• So,aGprotein-coupledreceptor(GPCR)isamembranereceptorthatislinkedinsomewaytoaGprotein.– There’stheGproteinandthere’sthereceptor(they’redifferent).
• Gprotein-linked receptorshavesevenαhelicesspanningthemembrane.
• Thesereceptorsareresponsibleforrelayingasignalfromaligandtotheinteriorofthecell(NOTrelayingtheliganditself).
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EnergyMolecules• BeforewelaunchintohowaGprotein-coupledreceptorworks,weneedtolookintoamoleculethatpowerstheGprotein.
• WhatamItalkingabout?• No,notATP…GTP!– ATP=Adenosinetriphosphate– GTP=Guanosine triphosphate
• Key:EachisanucleotidewithTHREEphosphategroups.
• Key:When“usedup,”themoleculeisreducedtoTWOphosphategroups,knownasadenosine/guanosine diphosphate.
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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.
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BacktoGProtein-CoupledReceptors• Inactive:– Thereceptorisspanningthemembrane.– TheGproteinisboundtoGDPandstucktotheinnermembrane.– Anenzymealsoexistsontheinnersurfaceofthecellmembrane.
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BacktoGProtein-CoupledReceptors• Activation:– TheorangeligandactivatestheGPCR,changingitstertiarystructure,whichbondstotheGprotein.
– GTPreplacesGDP,andtheGproteinmovestotheenzyme.– Theenzymepromptsthenextcellularresponses.
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BacktoGProtein-CoupledReceptors
• Deactivation:– TheenzymehydrolyzesGTPandremovesaphosphate.– TheGproteinisreleased.Theprocesscanstartagain.
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AndIcare…because?
• SowhyareGprotein-coupledreceptorsimportant?– YourvisionandsmellsensesuseGprotein-coupledreceptors.
– Diseaseslikebotulism,pertussis(whoopingcough),andcholeraproducetoxinsthatinterferewithGPCRs.
– Around60%ofmedicineworksbyaffectingGPCRs,andawholelotofdrugs(includingheroin)workthesameway.
– PTCpaper:tasted(ornot)?• YourabilitytotastePTCisbasedonwhetheryouhaveagenecodingforaGprotein-coupledreceptorforthatsubstance.
• NoGPCR,noPTCtaste.
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2.Tyrosine-KinaseReceptors
• Tyrosine-kinaseisanenzymestuckinthecellmembrane.
• ItsjobistodephosphorylateATPandmovethatphosphategrouptotheattachedtyrosine.
• IthasabindingsiteintheECMforsignalmoleculesandsingleαhelixinthemembrane.
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Tyrosine-KinaseReceptors• Inactive– Thetyrosine-kinasereceptorproteinsaretwoseparatemonomers,andrelayproteinsarenotactive.• Takeaguesswherethisisgoing…
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Tyrosine-KinaseReceptors• Activated– Aligandactivatesthemonomersandtheymakeadimer.– Oncejoined,thekinasedephosphorylatesATPandaddsthatphosphategrouptoitstyrosine(aminoacid),whichactivatesrelayproteins.
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Tyrosine-Kinasevs.GProtein
• GproteinstendtoelicitonlyonetypeofresponseperGprotein.
• Asingletyrosine-kinasereceptorcancausemultipleresponses.– Errantreceptortyrosine-kinaseshavebeenlinkedtocancer.
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3.IonChannelReceptors
• Theseareproteinchannelsthatopenonlywhenactivatedbyaligand.
• Nervecellsusethesefrequently.
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Receptors:BigIdeas• Versatility:Differentcelltypescanrespondtothesameligandindifferentways:
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Receptors:BigIdeas• Scaffolding:Someproteinsserveasintermediatesandholdrelayproteinstogether.
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Receptors:BigIdeas• Amplification:Asinglesignalmoleculecanleadtoamassiveresponse.– Thisisthepointofaphosphorylationcascade.
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SecondMessengers
• Signaltransductionpathwaysoftenactivatesecondmessengers.– Thesearemoleculeswithin cellsthatactassignalsjustliketheoriginalextracellular signal.
• Thethreemajorclassesofsecondmessengers:– Cyclicnucleotides– DAGandIP3– Calciumions(Ca2+)
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SecondMessenger:CyclicNucleotides
• Theenzymeadenylylcyclase isactivatedbyaGprotein.– Adenylylcyclase usesATPtomakecAMP,orcyclicAMP.
– AMP=adenosinemonophosphate• Similarly,guanylyl cyclase usesGTPtomakecGMP (cyclicGMP).
• Thesesecondmessengersthenservetoturnonotherresponseswithincells.
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SecondMessenger:IP3 andDAG
• DAGisdiacylglycerol whichstaysinthecellmembraneandactivatesotherenzymes,whichoftenuse…
• …IP3,whichisinositoltriphosphate.– ThishelpsreleaseCa2+ ions(whicharethemselvesconsideredasecondmessenger)fromtheER.
• Calciumions,bytheway,areusedwidelythroughoutthebody.– Includingmakingyourmusclescontract.
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AnotherView
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Aside:ClownAnemonefish
• You’veseenFindingNemo,right?• Whatthatmoviedidn’ttellyouisthatclownfish(clownanemonefish,officially)haveaninterestingstructureintheirsocialgroups.
• Thereisonlyonefemaleandonereproductivemale.– Allothersaresmallermaleswhosespermisinhibitedbythefemale.Allclownanemonefisharebornmale.
• Whenthefemaledies,thereproductivemalebecomesfemale witharushofestradiolhormone.– Thenextbiggest(notnecessarilyoldest)malebecomesthereproductivemale.
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Aside:ClownAnemonefish
• Whatdoesthismean?• Itmeansthat,assumingtherewerenootherindividualsinNemo’s group,afterNemo’s mom’sdeath,Nemo’s dadwillsoonbecomeNemo’s mom.
• Nemo,meanwhile,willbecomereproductiveandmatewithhisfathermother,untilheshe diesandNemo becomesfemale,perhapsmatingwithhisownoffspring.– Doryshouldhavejuststayedaway…
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TheCatch:Homeostasis
• Allthissignalingisgreat,butthere’sonemajorcatch:organismsstillneedtomaintainhomeostasis.
• Theycanachievethisthroughfeedbackloops.• Positivefeedback amplifiestheoriginalsignal.• Negativefeedback inhibitstheoriginalsignal.– Asyoumightguess,negativefeedbackisfarmoreusefultohomeostasis.
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NegativeFeedbackExamples
• Predator-PreyRelationships– Increaseinpreyleadstoanincreaseinpredators…whichdecreasesprey.
• BodyTemperature– Ariseinbodytemperatureissensedbyneuronswhichsignalthebrain,whichsendssignalstodilatethebloodvessels(vasodilation),decreasingtemperature.• Andmakingyouredintheface.
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NegativeFeedbackAnotherExample
• IfthepHintheduodenum(partoftheintestine)dropstoolow…
• …thecellsintheintestinereleasesecretin,achemicalsignal,intotheblood.
• Secretintravelstothepancreas,whichreleasesbicarbonate…
• …whichraisesthepH.
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PositiveFeedbackExamples
• Stampedes– Afewanimalsstarttostampede,causingmoretorun,leadingtoamassmovement.
• Uterinecontractions– Oxytocincausesuterinecontractions,whichmovesthefetusfurtherdownthebirthcanal,whichstimulatesmoreoxytocinrelease.
• Studentspackingupattheendofclass?
Awkwardstockphoto fromoldPowerPoint…atwhatexactlyarethey
alllooking?
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PositiveFeedbackAnotherExample
• Ifabreakoccursinabloodvessel…
• …plateletsadheretoitandreleasechemicals…
• …whichattractmoreplateletsuntiltheprocessends.
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PositiveFeedbackOnelastone…
• Theoceanisamajorcarbonsink.• Carbondioxidedissolvesbestincoldwater.• AsCO2 levelscausetemperaturestorise,moreCO2 precipitatesfromtheocean.
• MoreCO2 comingoutoftheoceanraisestemperatures…
• …whichreleasesmoreCO2.
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CouplingFeedbackLoops
• Rememberthatnegativefeedbackloopsarebestforhomeostasis.
• Topreventanylevelorratefromgettingtoohigh,youneedafeedbackloop.
• Topreventanylevelorratefromgettingtoolow,youneedanother feedbackloop.
• Key:Acoupled(ordouble)feedbackloopisneededtokeephomeostasis.– Let’slookatsomeexamples.Knowthekeycomponents.
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CalciumHomeostasis
BloodCa2+ high
Calcitoninreleased
BloodCa2+lowered
BloodCa2+ lowBloodCa2+raised
CalciumHomeostasis
ParathyroidHormone(PTH)released
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GlucoseHomeostasis
Bloodglucosehigh
Insulinreleased
Bloodglucoselowered
Bloodglucoselow
Bloodglucoseraised
GlucoseHomeostasis
Glucagonreleased
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Closure:FeedbackMechanismsPOGIL
• It’stimetoputourknowledgeoffeedbackmechanismstothetestusingaPOGIL.
• FeedbackMechanisms POGIL• Also:– TED:Anje-Margriet Neutel – FeedbackLoops:HowNatureGetsitsRhythms