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Transcript
Physiology Unit1 CELLSIGNALING:CHEMICALMESSENGERS ANDSIGNALTRANSDUCTIONPATHWAYS InPhysiologyToday CellCommunication • Homeostaticmechanismsmaintainanormalbalance ofthebody’sinternalenvironment • Controlsystems(NegativeFeedback)requirecellstobeable tocommunicatewitheachother • Cellularcommunicationismostlybychemical messengers(Ligands) • Neurotransmitters – Rapid – Shortdistance • Hormones – Slower – Longerdistance • Gases ParacrineAgents −Releasedbycell −Bindstoneighboringcells Autocrineagents −Releasedbycell −Bindstoselfcell LipidSolubleMessengers • Lipidsolublemessengers caneasilydiffusethrough theplasmamembrane • Messengersbindto intracellularreceptors • UsuallybindtoDNA • Activatedreceptoractsas atranscriptionfactor • Lipidsolublemessengers • Cortisol • Steroidhormones • Thyroidhormones WaterSolubleMessengers • Watersoluble messengerscannot diffusethroughthe plasmamembrane • Mustbindtoreceptorin theplasmamembrane • Watersoluble messengers – Peptidehormones – Neurotransmitters – Paracrine/autocrine compounds Receptors • Howcellsdetect chemicalmessengers • Receptorhasa bindingsiteforthe chemicalmessenger • Chemicalmessenger tellsthecellwhatto do CharacteristicsofReceptors • Specificity – Singlemessenger – Multiplemessengers • Affinity • Saturation • Competition – Antagonists – Agonists CompetitionforReceptors • Messengerswithasimilar structurecompetefor bindingsitesonreceptors • Antagonists – Blockstheendogenous messengerandpreventsthe response • Agonists – Bindstoreceptorand triggersthecellsresponse – Mimicsendogenous messenger RegulationofReceptors • Receptorsaresubjecttoregulation – Numberofreceptors – Affinityofreceptors • Down-regulation – Persistent,high[chemicalmessenger] – Desensitizing • Up-regulation – Prolonged,low[chemicalmessenger] – Hypersensitivity LigandGatedIonChannels • Receptoractivation opensanionchannel • Increasesmembrane permeabilityofthation • Iondiffusesacrossthe plasmamembrane • Changesmembrane potential • Examples: • Manyneurotransmitters ReceptorTyrosineKinases • Intrinsicenzymeactivity • Regulates • Cellproliferation • Celldifferentiation • Apoptosis • Receptoractivation includesactivationofthe enzyme • Examples • Growthfactors • Insulin ReceptorsThatActivateJAKKinase • Receptoractivation activatestheassociated JAKkinase • JAKkinases phosphorylate transcriptionfactors • Examples – Prolactin – GH – Manycytokines G-Protein-CoupledReceptors • Verycommon • G-proteincomplexbound toareceptor • Receptoractivation resultsindissociationof theαsub-unit – α-sub-unitactivatesan ion channelor anenzyme in theplasmamembrane • Examples: – Manyneurotransmitters – Manyhormones WaterSolubleMessengers PathwayComponents • PathwayComponents 1. ReceptorActivation 2. Receptoractivationgeneratesasecondchemical messengerinthecytoplasm 3. Signaltransduction:aseriesofchemicalreactionsthat resultinthecellsresponse • Proteinkinase – Anyenzymethatphosphorylatesotherenzymesor proteinsbytransferringaphosphategroupfromATP – Activatestheenzymeorprotein • Changestheconformation ofthephosphorylatedprotein SignalTransductionPathways • Receptoractivationistheinitialstep – Messenger-receptorbindingcausesa conformationchangeinthereceptor – Examplesofacellsresponse: – – – – – – – Permeability Transportproperties Voltagechangeinthemembrane Cellmetabolism Cellsecretory activity Cellscontractileactivity Proteinsynthesis SignalTransduction • Signaltransduction pathwaysconvert chemicalsignalstoa biologically meaningfulresponse • Sequenceofevents frombindingofa chemicalmessenger tothecellsresponse 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 – PhospholipaseCsplitsaplasmamembrane phospholipidtodiacylglycerol(DAG) • Action – ActivatesproteinkinaseC • ProteinkinaseCactivatesotherintracellularproteins InositolTriphosphate(IP3) 2nd messenger • Source – 1st messengeractivatesaG-proteincoupled receptor – G-proteinactivatesPhospholipaseC – PhospholipaseCsplitsaphospholipidtoinositol triphosphate(IP3) • Action - IP3 BindstoligandgatedCa2+channelsonthe smoothER - Ligand-gatedCa2+channelsopenandincrease cytoplasmic[Ca2+] DAGandIP3 2nd messengers ProteinKinaseCis activatedbyDAGand Ca2+ 2+ Calcium(Ca ) 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 2+ Calcium(Ca ) 2nd messenger • Remember…active transportsystemsinthe plasmamembraneand organelles maintain lowcytoplasmic[Ca2+] ArachidonicAcid 2nd messenger • Source – 1st messengerbindstoag-coupledreceptor – G-proteinactivatesPhospholipase2 – Phospholipase2splitsoffarachidonicacidfroma membranephospholipid • Action – Produceseicosanoids • Cyclooxygenase(COX)pathwayorlipoxygenase(LOX)pathway • Eicosanoidsmayactas2nd messengersoraslocal paracrine/autocrineagents ArachidonicAcid 2nd messenger • NSAIDS blocktheCOX pathway • reducepain,fever, inflammation • Adrenalsteroidsinhibit phospholipaseA2 • blockstheproductionofall eicosanoids • Eicosanoids areproduced fromarachidonicacid – Prostaglandins – Thromboxanes – Leukotrines Eicosanoids Prostaglandins,Thromboxanes,Leukotrines • SignalingmoleculesinCNS – Hormones – Paracrine/paracrineagents • • • • Sometimescalled“super” hormones DerivedfromOmega-3andOmega-6fattyacids Involvedininflammationandimmunity Verycomplexcontrolsystems vCortisolinhibitseicosanoidproduction StoppingSignalTransductionPathways • Chronicoverstimulationincellscanbe detrimental • Presenceof2nd messengersaretransient • Physiologicalcontrolstostopreceptoractivation 1. Enzymesinthevicinitymetabolizethe1st messenger 2. Phosphorylatingthereceptor • Maydecreaseit’saffinityforthemessenger • MaypreventfurtherbindingofG-proteinsbindingtothe receptor 3. Endocytosisofmessenger-receptorcomplex
