Extracellular receptors g-protein coupled receptors

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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Masters P rogrammes at the University of Pcs and at the University of Debrecen Identification number : TMOP-4.1.2-08/1/A-2009-0011. - PowerPoint PPT Presentation

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Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Masters Programmesat the University of Pcs and at the University of DebrecenIdentification number: TMOP-4.1.2-08/1/A-2009-0011Extracellular receptorsg-protein coupled receptorsTmea Berki and Ferenc BoldizsrSignal transductionManifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Masters Programmesat the University of Pcs and at the University of DebrecenIdentification number: TMOP-4.1.2-08/1/A-2009-0011Ligand-bindingG C-terminal tailOther G surfacesHelix 8 (G-binding)G -bindingInteraction surfaceIL1IL2IL3EL1EL3EL2Extracellular loops (EL1-3)Intracellular loops (IL1-3)NCGRK phosphorylation(Desensitization)PKC phosphorylation(Desensitization)PKC phosphorylation(Desensitization)Palmitoylation(Lipid raft localization)N-Glycosylation(Receptor folding, trafficking)E/DRY Motif(Receptor activity andprotein-protein interactions)Plasma membraneTM1TM2TM3TM4TM5TM6TM7Transmembrane helix(TM1-7)TM47-transmembrane-spanning receptors (7-TM) TMOP-4.1.2-08/1/A-2009-001137-transmembrane-spanning receptors (7-TM)Class A: Rhodopsin-likeClass B: Secretin familyClass C: Glutamate and GABA (metabotropic)FrizzledAdhesion familyTMOP-4.1.2-08/1/A-2009-00117-transmembrane-spanning receptors (7-TM) GPCR superfamily(791 genes)Class A(662)Class B(15)Class C(22)Others(92)Endogenous ligand/Orphan(271)Olfactory/Pheromone(391)TMOP-4.1.2-08/1/A-2009-00117-TM ligandsClass AClass BClass CFrizzledAdhesionProstaglandinsGlucagonGlutamateWntChondroitin-sulfateThromboxaneGnRHGABAHedgehogSerotoninePTHSweet tastesBitter tastesDopamineCRHSecretin HistamineCatecholaminesAch (M)RhodopsinMelatoninChemokinesBradykininSomatostatinOpioidVasopressinTMOP-4.1.2-08/1/A-2009-0011Inactive 7-TM receptorSide perspectiveIntracellular perspectiveTM1TM2TM3TM4TM5TM6TM7Helix 8IL1IL3EL1EL2EL3NCGa-binding surfaceTM1TM4TM5TM6TM7Helix 8IL 1IL2IL3EL1EL2EL 3NCTM2TM3Intracellular loopsExtracellular loopsNon-covalent bondIL2TMOP-4.1.2-08/1/A-2009-0011TM1TM2TM4Helix 8IL1IL2IL3EL1EL2EL3NCTM7TM6TM3TM5GaTM1TM5TM6TM7Helix 8NCTM4TM2GTM3GaC-terminal tailof GaAgonistActive 7-TM receptorSide perspectiveIntracellular perspectiveTMOP-4.1.2-08/1/A-2009-0011GDPgbagbGTPaGTPgbaGDPgbaPlasma membraneCytoplasmGDPGTPG-protein coupled receptor(GPCR)Signal moleculeInactive G-proteinActivated G-protein subunitsGTPgba7-TM receptors bind to G-proteins(G-protein-coupled receptors, GPCR)TMOP-4.1.2-08/1/A-2009-00119G-proteinsCellular responsecAMPGDPGsGDPGiAdenylylcyclase(+) (-)GTPGsGTPGiATPProtein kinase AInactive Protein kinase AActive ProteinProteinOHP5-AMPPhosphodiesteraseStimulatoryhormoneInhibitoryhormoneRsRiTMOP-4.1.2-08/1/A-2009-0011GDPGTPGiG-protein coupled receptor(GPCR)PhospholipasesIon channelsActivates RhoIon channelsPI3KPhospholipasesAdenylyl cyclasesReceptor kinasesGTPGsGTPGqGTPG12/13GTPCa2+PLCPIP2DAGIP3cAMPAdenylylcyclaseATPcAMPAdenylylcyclaseATPPlasma membraneCytoplasmG-proteinsTMOP-4.1.2-08/1/A-2009-001111G-proteinsGTP-binding proteinsGTPase activity: they hydrolyse GTP to GDPInactive form: GDP-boundActive form: GTP-boundHeterotrimeric: a, b, g subunitsMonomeric: products of ras proto-oncogensg subunit contains C terminal isoprenyl chains: anchoring in the plasma membraneTMOP-4.1.2-08/1/A-2009-0011G-protein signaling 1Ga signalingGs: stimulate adenylyl-cyclase cAMP Gi: inhibit adenylyl-cyclase cAMP Gq: stimulate PLCG12: Rho-GEF 2Gb, g signalingK+ and Ca2+ channels, PI3K isoformsTMOP-4.1.2-08/1/A-2009-0011GPCR regulationPKA feedback phosphorylationG-protein receptor kinases (GRK1-7): regulate 7TM activation by phosphorylation of the C terminus of the receptors Translocation: the active receptor with the surrounding membrane is internalized dephosphorylated in acidic vesicles and recycled to the surfaceArrestin linking: binding of arrestin molecules inhibit the binding of Gs proteins to the receptors (eg. rhodopsin in retina); + activation of alternative pathways: MAPK, PI3-K, PKB/Akt, SrcTMOP-4.1.2-08/1/A-2009-0011Monomeric G-proteins (Ras family)First found as transforming oncogenes: Harvey (H-Ras) and Kirsten (K-Ras) sarcoma viruses; Rat sarcomaN-Ras found in human neuroblastoma189 AAAnchored to the membrane through lipid chainsMutations in the Ras family is found in 20-30% of all human tumors

TMOP-4.1.2-08/1/A-2009-0011Ras regulationGuanine-nucleotide exchange factors (GEFs): catalyse the GDP-GTP exchange of Ras Activation

GTPase activating protein (GAP): the intrinsic GTPase activity of Ras is weak, enhanced by GAP InactivationTMOP-4.1.2-08/1/A-2009-0011Ras function MAPK cascadeSignaling through growth factor receptorsRas-Raf-MEK-ERK (Mitogen-activated protein kinase = MAPK cascade)Increased activity (= constitutively active Ras) promotes tumor transformationG-nucleotide exchange (point mutations)GTPase activity (point mutations or lack of GAP)TMOP-4.1.2-08/1/A-2009-0011Ras-MAPK cascadeRASPlasma membraneSOSGRB2Transcriptional regulationYYYYYYGrowth factor/HormoneReceptor PTKCytoplasmActiveRASElk-1RAFMEK1/2ERK1/2Sap1aNetAdaptorGuanine nucleotideexchange factor(GEF)TMOP-4.1.2-08/1/A-2009-0011

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