Post on 02-Oct-2021
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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