CELLSIGNALING:CHEMICALMESSENGERSANDSIGNALTRANSDUCTIONPATHWAYS

PhysiologyUnit1

InPhysiologyToday

CellCommunication• Homeostaticmechanismsmaintainanormalbalanceofthebody’sinternalenvironment

• Controlsystems(NegativeFeedback)requirecellstobeabletocommunicatewitheachother

• Cellularcommunicationismostlybychemicalmessengers(Ligands)

• Neurotransmitters � ParacrineAgents– Rapid −Releasedbycell– Shortdistance −Bindstoneighboringcells

• Hormones � Autocrineagents– Slower −Releasedbycell– Longerdistance −Bindstoselfcell

• Gases

LipidSolubleMessengers• Lipidsolublemessengers

caneasilydiffusethroughtheplasmamembrane

• Messengersbindtointracellularreceptors• UsuallybindtoDNA

• Activatedreceptoractsasatranscriptionfactor

• Lipidsolublemessengers• Cortisol• Steroidhormones• Thyroidhormones

WaterSolubleMessengers• Watersolublemessengerscannotdiffusethroughtheplasmamembrane

• Mustbindtoreceptorintheplasmamembrane

• Watersolublemessengers– Peptidehormones– Neurotransmitters– Paracrine/autocrinecompounds

Receptors

• Howcellsdetectchemicalmessengers

• Receptorhasabindingsiteforthechemicalmessenger

• Chemicalmessengertellsthecellwhattodo

CharacteristicsofReceptors

• Specificity– Singlemessenger– Multiplemessengers

• Affinity• Saturation• Competition– Antagonists– Agonists

CompetitionforReceptors• Messengerswithasimilar

structurecompeteforbindingsitesonreceptors

• Antagonists– Blockstheendogenous

messengerandpreventstheresponse

• Agonists– Bindstoreceptorand

triggersthecellsresponse– Mimicsendogenous

messenger

RegulationofReceptors

• Receptorsaresubjecttoregulation– Numberofreceptors– Affinityofreceptors

• Down-regulation– Persistent,high[chemicalmessenger]– Desensitizing

• Up-regulation– Prolonged,low[chemicalmessenger]– Hypersensitivity

LigandGatedIonChannels

• Receptoractivationopensanionchannel

• Increasesmembranepermeabilityofthation

• Iondiffusesacrosstheplasmamembrane

• Changesmembranepotential

• Examples:• Manyneurotransmitters

ReceptorTyrosineKinases• Intrinsicenzymeactivity• Regulates• Cellproliferation• Celldifferentiation• Apoptosis

• Receptoractivationincludesactivationoftheenzyme

• Examples• Growthfactors• Insulin

ReceptorsThatActivateJAKKinase• ReceptoractivationactivatestheassociatedJAKkinase

• JAKkinasesphosphorylatetranscriptionfactors

• Examples– Prolactin– GH– Manycytokines

G-Protein-CoupledReceptors

• Verycommon• G-proteincomplexboundtoareceptor

• Receptoractivationresultsindissociationoftheαsub-unit– α-sub-unitactivatesan ionchannelor anenzyme intheplasmamembrane

• Examples:– Manyneurotransmitters– Manyhormones

WaterSolubleMessengersPathwayComponents

• PathwayComponents1. ReceptorActivation2. Receptoractivationgeneratesasecondchemical

messengerinthecytoplasm3. Signaltransduction:aseriesofchemicalreactionsthat

resultinthecellsresponse

• Proteinkinase– AnyenzymethatphosphorylatesotherenzymesorproteinsbytransferringaphosphategroupfromATP

– Activatestheenzymeorprotein• Changestheconformation ofthephosphorylatedprotein

SignalTransductionPathways

• Receptoractivationistheinitialstep–Messenger-receptorbindingcausesaconformationchangeinthereceptor

– Examplesofacellsresponse:– Permeability– Transportproperties– Voltagechangeinthemembrane– Cellmetabolism– Cellsecretory activity– Cellscontractileactivity– Proteinsynthesis

SignalTransduction

• Signaltransductionpathwaysconvertchemicalsignalstoabiologicallymeaningfulresponse

• Sequenceofeventsfrombindingofachemicalmessengertothecellsresponse

CyclicAMP(cAMP)2ndmessenger

• Source– 1stmessengeractivatesaG-proteincoupledreceptor– G-proteinactivatesadenylylcyclase– AdenylylcyclaseconvertsATPtocAMP

• Action:– cAMPactivatescAMP-dependentproteinkinaseA

• ProteinkinaseAactivatesalargenumberofdifferentproteins• Initiatesanamplificationcascade

– cAMPmayalsode-activateenzymes

CyclicAMP(cAMP)2ndmessenger

Phosphodiesterase deactivatescAMPtoAMP

SignalAmplificationbycAMP

Diacylgylerol(DAG)2nd messenger

• Source– 1st messengeractivatesaG-proteincoupledreceptor– G-proteinactivatesPhospholipaseC– PhospholipaseCsplitsaplasmamembranephospholipidtodiacylglycerol(DAG)

• Action– ActivatesproteinkinaseC• ProteinkinaseCactivatesotherintracellularproteins

InositolTriphosphate(IP3)2nd messenger

• Source– 1st messengeractivatesaG-proteincoupledreceptor

– G-proteinactivatesPhospholipaseC– PhospholipaseCsplitsaphospholipidtoinositoltriphosphate(IP3)

• Action- IP3 BindstoligandgatedCa2+channelsonthesmoothER- Ligand-gatedCa2+channelsopenandincreasecytoplasmic[Ca2+]

DAGandIP32nd messengers

ProteinKinaseCisactivatedbyDAGand

Ca2+

Calcium(Ca2+)2nd messenger

• Source- Intheplasmamembrane:

- LigandgatedCa2+channels- VoltagegatedCa2+channels- G-proteinactivatesCa2+channels

- Ca2+ releasedfromthesmoothER(mediatedbyIP3 orCa2+enteringthecytoplasm)

- ActivetransportofCa2+ isinhibitedbya2nd messenger• Action- Ca2+ activatescalmodulin

- Activatescalmodulin-dependentproteinkinases- Ca2+ bindstoandaltersproteinactivitydirectly

Calcium(Ca2+)2nd messenger

• Remember…activetransportsystemsintheplasmamembraneandorganellesmaintainlowcytoplasmic[Ca2+]

ArachidonicAcid2nd messenger

• Source– 1st messengerbindstoag-coupledreceptor– G-proteinactivatesPhospholipase2– Phospholipase2splitsoffarachidonicacidfromamembranephospholipid

• Action– Produceseicosanoids

• Cyclooxygenase(COX)pathwayorlipoxygenase(LOX)pathway• Eicosanoidsmayactas2nd messengersoraslocalparacrine/autocrineagents

ArachidonicAcid2nd messenger

• NSAIDS blocktheCOX pathway• reducepain,fever,

inflammation• Adrenalsteroidsinhibit

phospholipaseA2• blockstheproductionofall

eicosanoids• Eicosanoids areproduced

fromarachidonicacid– Prostaglandins– Thromboxanes– Leukotrines

EicosanoidsProstaglandins,Thromboxanes,Leukotrines

• SignalingmoleculesinCNS– Hormones– Paracrine/paracrineagents

• Sometimescalled“super” hormones• DerivedfromOmega-3andOmega-6fattyacids• Involvedininflammationandimmunity• Verycomplexcontrolsystems

vCortisolinhibitseicosanoidproduction

StoppingSignalTransductionPathways

• Chronicoverstimulationincellscanbedetrimental• Presenceof2nd messengersaretransient

• Physiologicalcontrolstostopreceptoractivation1.Enzymesinthevicinitymetabolizethe1st messenger2.Phosphorylatingthereceptor

• Maydecreaseit’saffinityforthemessenger• MaypreventfurtherbindingofG-proteinsbindingtothereceptor

3.Endocytosisofmessenger-receptorcomplex