signal transduction · 2016. 10. 13. · figure 6.8a g protein -coupled signal transduction slid e...

Biol 219Lect 18Fall2016 Dr Scott

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Signal Transduction

ImportantConcepts

• Cell-to-cellcommunication• Signalpathways•Modulationofsignalpathways• Homeostaticreflexpathways

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Cell-to-CellCommunication:Overview:PhysiologicalSignals

• ElectricalSignals• Changes inthemembrane potential

• ChemicalSignals• Secreted bycells intotheECF• Responsible formostcommunication inthebody

• ChemicalSignalsareLigands• Targetcells(Targets),respondtoSignals

Cell-to-CellCommunication:Overview:Methodsofcommunication

• LocalCommunication• GapJunctions(cytoplasmicbridges)

• Contactdependent (cell-cell contacts)

• Localcommunicationusesparacrineandautocrinesignals

• Longdistancecommunicationuseschemicalandelectricalsignals


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Gap junctions formdirect cytoplasmicconnections betweenadjacent cells.

Contact-dependent signalsrequire interaction betweenmembranemolecules ontwo cells.


Autocrine signals actonthesamecellthatsecretedthem.Paracrine signalsaresecretedbyonecellanddiffusetoadjacentcells.

ReceptorEndocrine System

Endocrinecell

Cellwithoutreceptor

Noresponse

Cellwith

receptor Targetcell

Response

Hormones aresecretedbyendocrineglandsorcellsintotheblood.Onlytargetcellswithreceptorsforthehormonerespondtothesignal.


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Figure6.1eCommunicationintheBody


Electricalsignal

Neuron

Targetcell Response

Neurotransmitters arechemicals secreted byneurons that diffuseacross asmall gap to the targetcell.

Long-DistanceCommunication• Thenervoussystemusesacombinationofchemicalandelectricalsignalsforlong-distancecell-to-cellcommunication

• Neurocrines arechemicalsignalssecretedbyneurons• Neurotransmitters• Neuromodulators• Neurohormones



Blood

Neuron

Noresponse

Response

Cellwithoutreceptor

Cellwith

receptorNeurohormones arechemicalsreleasedbyneuronsintothebloodforactionatdistanttargets.

Cytokines• Peptides,synthesizedandsecretedbyallnucleatedcellsinresponsetostimuli

•Mayactasbothlocalandlong-distancesignals

• Indevelopmentanddifferentiation,cytokinesusuallyfunctionasautocrineorparacrinesignals

• Instressandinflammation,somecytokinesmayactonrelativelydistanttargets



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SignalPathways

ReceptorproteinsØAcellrespondstoaparticularchemicalsignalonlyifthetargethasareceptor,abindingprotein


TheSignalPathway

• Thechemical signal isaligand thatbindstothereceptor andisthe firstmessenger

• Ligand-Receptor bindingactivates the receptor

• The receptor activatesoneormore intracellularsignalmolecules

• The last signalmolecule modifiesexistingproteinsorinitiates thesynthesisofnewproteins

Figure6.2Signalpathways


ReceptorsAreLocatedInsidetheCellorontheCellMembrane

• Lipophilicsignalmolecules• Diffusethroughthecellmembrane• Bindtoreceptorsinthecytosolornucleus

• Lipophobic signalmolecules• Bindtoreceptorsonthecellmembrane



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MembraneReceptorsFourgroupsofmembranereceptors• Ligand-gated• GProtein-coupled• Receptor-enzymes• Integrinreceptors• Transmissionofsignalfromonesideofthemembranetotheotheriscalledsignaltransduction

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Intracellular Signal Receptors

Receptor incytosolReceptorinnucleus

Lipophilic signal molecules diffusethroughthecellmembrane.

Binding tocytosolicornuclearreceptorstriggers

Slower responsesrelated tochangesingeneactivity


Cell Membrane Receptors(b)

Extracellular signalmolecule binds toacellmembranereceptor.

Bindingtriggers

Rapid cellularresponses


Four Categories of Membrane Receptors

Extrace llu larsignal

mo le cu le s

Channe l

EC F

Re ce p to r

IC F

Re ce p to r In te grin

Ce llmembrane

Gp ro te in Enzyme

Anchorp ro te in

Cytoske le ton

Integrin receptorReceptor-enzymeG protein– coupled receptorReceptor-channel

Ligand b ind ingope nso rclo se sthe channe l.

Ligand b ind ing to aGp ro tein–coup le d re ce p to ropensan ionchanne lo ralte rse nzyme activity.

Ligand b ind ing to are ce p to r-e nzyme activate san in trace llu lare nzyme .

Ligand b ind ing to in tegrin re ce p to rsalte rse nzyme so r the cytoske le ton .

Catalytic receptors


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MembraneProteinsFacilitateSignalTransduction

ØSignaltransduction

• Extracellularsignalisthefirstmessenger

• Intracellularsignalisthesecondmessenger

• Transducerconvertsasignalfromoneformtoanother


MembraneProteinsFacilitateSignalTransduction

ØTransductionpathway

• Cascadeofactivationsteps

• Amplificationofsignals

•Mostcommonamplifierenzymesandsecondmessengers


Figure6.4Signaltransduction


Figure6.5aBiologicalsignaltransduction



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Figure6.5bBiologicalsignaltransduction

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Figure 6.6bSignalTransduction:Cascades andAmplification


Signal amplificationallowsasmallamountofsignal tohavealargeeffect.

Receptor-ligandcomplexactivatesan

amplifierenzyme(AE).

ExtracellularFluid

IntracellularFluid

Cellmembrane

L

R

AE

Oneligandisamplifiedintomanyintracellularmolecules.

Figure6.6cSignalTransduction:CascadesandAmplification



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MostRapidSignalPathwaysChangeIonFlowthroughChannels

• Foundmostlyinnerveandmuscle

• Ligandbindingtoareceptor-channelproteinchangespermeabilitytoanion

• Rapidflowofanioninoroutofthecellbringsaboutarapidresponsefromthecell.


Figure 6.7Signaltransductionusingionchannels


GProtein–CoupledReceptors(GPCR)• Membrane-spanning proteins• Cytoplasmic tail linked toGprotein,athree-parttransducermolecule

• Gprotein-coupledadenylyl cyclase-cAMP systemisthesignal transductionsystemformanyproteinhormones

• Gprotein-coupled receptorsusesome lipidsecondmessengers: e.g., diacylglycerol (DAG)andinositoltrisphosphate (IP3)


GProtein–CoupledReceptors(GPCR)

•WhenGproteinsareactivated,they

•Openionchannelsinthemembrane

• Alterenzymeactivityonthecytoplasmicsideofthemembrane



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Sl id e1Figure 6.8a G protein-coupled signal transductionGPCR-Adenylyl Cyclase Signal Transduction and Amplification

Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase

ATP

cAMP

ProteinkinaseA

Phosphorylatedprotein

Cellresponse

Signalmoleculebinds toG protein–coupledreceptor(GPCR),whichactivates theG protein.

G proteinturns onadenylylcyclase,anamplifierenzyme.

Adenylylcyclase converts ATPtocyclicAMP.

cAMP activates proteinkinaseA.

ProteinkinaseAphosphorylatesotherproteins,leadingultimatelytoacellularresponse.

Figure 6.8a G protein-coupled signal transduction


Sl id e2

GPCR-Adenylyl Cyclase Signal Transduction and Amplification

Ones ignalmolecule

Gprotein

GPCR




Sl id e3


Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase





Sl id e4


Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase

ATP

cAMP





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Sl id e5


Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase

ATP

cAMP

ProteinkinaseA







Sl id e6


Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase

ATP

cAMP

ProteinkinaseA









Sl id e7


Ones ignalmolecule

Gprotein

GPCR

Adenylylcyclase

ATP

cAMP

ProteinkinaseA


Cellresponse







Sl id e1

Figure 6.8b G protein-coupled signal transduction

GPCR-Phospholipase C Signal Transduction

Signalmo le cu le

Re ce p to rGp ro te in

PLC

IP 3

DAGPKC

Membrane phospho lip id

Phosphorylate dpro te in

Ce llu larre sponse

sto re sER

Ca2+ Ca2+

P ro te in +P i In tra cellu la rflu id

Ce llmembrane

Extra cellu la rflu id

KEY

Signal mo le cu leactivate s re ce p to rand associate dGp ro te in .

Gp ro te in activate sphospho lipase C (P LC ),an amp lifie re nzyme .

P LC conve rtsmembrane phospho -l ip id s in to d iacylglyce ro l (DAG),wh ichremains in the membrane ,and IP 3,wh ich d iffu se s in to the cytop lasm.

DAGactivate s p ro te inkinase C (PKC ),wh ichphosphorylate sp ro te in s.

IP 3 cause s re le aseo fC a2+ fromorgane lle s, cre atingaCa2+ signal.

P LCDAGPKCIP 3ER

= phospho lipase C= d iacylglyce ro l= p ro te in kinase C= inosito l trisphosphate= e ndop lasmic re ticu lum


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Sl id e2


Signalmo le cu le


In tra cellu la rflu id

Ce llmembrane


KEY


P LCDAGPKCIP 3ER

= d iacylglyce ro l= p ro te in kinase C= inosito l trisphosphate= e ndop lasmic re ticu lum

= phospho lipase C


Sl id e3


Signalmo le cu le


PLC


Ce llmembrane


KEY



P LCDAGPKCIP 3ER


= phospho lipase C


Sl id e4


Signalmo le cu le


PLC

IP 3

DAG



Ce llmembrane


KEY




PLCDAGPKCIP 3ER


= phospho lipase C


Sl id e5


Signalmo le cu le


PLC

IP 3

DAGPKC



Ce llu larre sponse


Ce llmembrane


KEY





P LCDAGPKCIP 3ER


= phospho lipase C


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Sl id e6


Signalmo le cu le


PLC

IP 3

DAGPKC



Ce llu larre sponse

sto re sER

Ca2+ Ca2+


Ce llmembrane


KEY





IP 3 cause s re le aseo fC a2+ fromorgane lle s, cre atingaCa2+ signal.

P LCDAGPKCIP 3ER


= phospho lipase C

Receptor-EnzymesAreProteinKinasesorGuanylylCyclases

LigandsbindproteinkinasesthataddphosphategroupstotargetproteinsorguanylylcyclasethatconvertsGTPtocGMP


Figure6.9Receptor-enzymes:Thetyrosinekinasereceptor


Signalmolecule bindstosurfacereceptor

activates

Tyrosine kinaseoncytoplasmicside

ECF

Cellmembrane

L

R

TK

Activebinding site

PhosphorylatedproteinATP

Protein Protein P

+ ADPICF

+

Integrins

•Membrane-spanningproteins

•Outsidethecell,integrins bindtoextracellularmatrixproteinsortoligands

• Insidethecell,integrins attachtothecytoskeletonviaanchorproteins



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Figure 6.3cTarget cellreceptors maybeonthecellsurface orinsidethecell


Four Categories of Membrane Receptors

Extrace llu larsignal

mo le cu le s

Channe l

EC F

Re ce p to r

IC F

Re ce p to r In te grin

Ce llmembrane

Gp ro te in Enzyme

Anchorp ro te in

Cytoske le ton

Integrin receptorReceptor-enzymeG protein– coupled receptorReceptor-channel

Ligand b ind ingope nso rclo se sthe channe l.

Ligand b ind ing to aGp ro tein–coup le d re ce p to ropensan ionchanne lo ralte rse nzyme activity.

Ligand b ind ing to are ce p to r-e nzyme activate san in trace llu lare nzyme .

Ligand b ind ing to in tegrin re ce p to rsalte rse nzyme so r the cytoske le ton .

Catalytic receptors

Figure6.10SummaryMapofSignalTransduction


TestYourKnowledge

Whydosomenormalcellsfailtorespondtoachemicalsignal?

• A)Chemical signalsareonlydelivered tospecificcells.

• B)Somecells lack thenecessary receptors.

• C)Somecellsarecompletely without receptors.

• D)Somecellsarecompletely without ligands.

• E)Signal chemicalsoftenbreakdownbeforereaching adistanttarget.


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Whydosomenormalcellsfailtorespondtoachemicalsignal?

• A)Chemical signalsareonlydelivered tospecificcells.

ØB)Somecells lack thenecessary receptors.

• C)Somecellsarecompletely without receptors.

• D)Somecellsarecompletely without ligands.

• E)Signal chemicalsoftenbreakdownbeforereaching adistanttarget.

Lipophilichormones• A)bindtoreceptors onthesurfaceofthecell.

• B)functionbywayofa secondmessenger system.

• C)cannotdiffusethrough thecellmembrane.

• D)bindtoreceptors insidethecytoplasmornucleus.

• E)functionbyactivatingcAMP.

Lipophilichormones• A)bindtoreceptors onthesurfaceofthecell.

• B)functionbywayofa secondmessenger system.

• C)cannotdiffusethrough thecellmembrane.

ØD)bindtoreceptors insidethecytoplasmornucleus.

• E)functionbyactivatingcAMP.

Whenadenylylcyclaseisactivated,• A)calcium ionsare released fromintracellularstores.

• B)cAMP isformed.

• C)cAMP isbrokendown.

• D)proteinkinasesare metabolized.

• E)steroidsareproduced.


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Whenadenylylcyclaseisactivated,• A)calcium ionsare released fromintracellularstores.

ØB)cAMP isformed.

• C)cAMP isbrokendown.

• D)proteinkinasesare metabolized.

• E)steroidsareproduced.

Themostimportantfactordeterminingwhichtypeofreceptorasignalmoleculewillbindtois

• A)the lipidsolubilityofthe ligand.

• B)thesizeoftheligand.

• C)thesizeofthereceptor molecule.

• D)thelocationofthe receptormolecule.

Themostimportantfactordeterminingwhichtypeofreceptorasignalmoleculewillbindtois

ØA)the lipidsolubilityofthe ligand.

• B)thesizeoftheligand.

• C)thesizeofthereceptor molecule.

• D)thelocationofthe receptormolecule.

• https://www.youtube.com/watch ?v=qOVkedxDqQo

signal transduction · 2016. 10. 13. · figure 6.8a g protein -coupled signal transduction slid e...

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