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G-protein-linked receptors

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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G-protein-linked receptors

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction G-protein-linkedreceptors

  3. Nomenclature • G-protein-coupled receptors (GPCRs) • Seven-transmembrane domain receptors • 7-TM receptors • Heptahelical receptors • Serpentine receptor • G protein-linked receptors (GPLR)

  4. 7-transmembrane-spanning receptors(7-TM) N N-Glycosylation (Receptor folding, trafficking) Ligand-binding GαC-terminaltail EL1 EL2 EL3 Extracellularloops (EL1-3) Gα -binding Other Gαsurfaces Helix 8 (Gβ-binding) Plasmamembrane Interactionsurface TM 1 TM 2 TM 3 TM 4 TM 4 TM 5 TM 6 TM 7 Transmembranehelix (TM1-7) PKC phosphorylation (Desensitization) Intracellularloops (IL1-3) IL1 IL2 IL3 Palmitoylation (Lipid raft localization) E/DRY Motif (Receptor activity and protein-protein interactions) GRK phosphorylation (Desensitization) PKC phosphorylation (Desensitization) C

  5. GPCR

  6. Structure of 7-TM receptors N EL 3 Agonist N EL2 EL1 Intracellularloops TM 7 TM 5 TM 6 InactiveGPCR Active GPCR TM 1 TM 6 TM 7 TM 5 Sideperspective TM 1 TM 3 TM 2 C TM 4 Helix8 TM 3 TM 2 C TM 4 Helix8 Gα IL3 Extracellularloops Ga IL 1 IL2 C-terminal tail of Ga C N EL3 Helix8 TM 6 TM 7 TM 7 IL3 TM 6 TM 1 TM 1 TM 5 TM 5 EL2 TM 3 TM 3 IL1 Intracellularpersective Ga TM 2 TM 2 TM 4 TM 4 EL1 Non-covalent bond IL2 C N Helix8 EL3 IL3 Ga-binding surface IL1 EL2 EL1 IL2

  7. GPCR subtypes • Class A (or 1) – Rhodopsin-like • Class B (or 2) – Secretin receptor family • Class C (or 3) – Metabotropic glutamate/pheromone • Class D (or 4) – Fungal mating pheromone receptors • Class E (or 5) – Cyclic AMP receptors • Class F (or 6) – Frizzeled/Smoothened

  8. Activation of G-protein-coupled receptors (GPCR) Signal molecule G-protein coupled receptor (GPCR) g g g a a a b b b GDP GDP GTP Inactive G-protein g b GDP GTP Plasma membrane g b Cytoplasm a a GTP GTP Activated G-protein subunits

  9. G-proteins G-protein coupled receptor (GPCR) Plasmamembrane Cytoplasm g a b GDP a GTP g b Ion channels PI3K Phospholipases Adenylylcyclases Receptor kinases G12/13 Gi Gs Gq GTP GTP GTP GTP Adenylyl cyclase Adenylyl cyclase PLC PIP2 DAG Activates Rho ATP cAMP ATP cAMP IP3 Phospholipases Ion channels Ca2+

  10. G-protein heterotrimer

  11. Catecholamine hormon synthesis +H3N +H3N CO2– +H3N CO2– OH OH DOPA Tyrosine hydroxylase decarboxylase OH OH OH Dihydroxyphenilalanine(L-DOPA) Tyrosine Dopamine H2+ +H3N N H3C OH OH Phenethanolamine Dopamine HO HO N-methyltransferase β-hydroxylase OH OH Dopamine Epinephrine

  12. Epinephrine and analogues OH OH H H OH NH2 HO N N H CH3 CH3 N .HCL .HCL .H2SO4 CH3 CH3 HO HO CH3 Pseudoephedrine HCL Tyramine HCL 2 Epinephrine (adrenaline) Ephedrine sulphate OH NH2 NH2 NH2 .H2SO4 .H2SO4 .H2SO4 CH3 CH3 2 2 2 Dexamfetamine sulfate Amfetamine sulfate Phenylethanolamine sulfate OH H HO CH3 N OH OH H H .H2SO4 HO CH3 N CH3 N CH3 .H2SO4 HO .HCL CH3 CH3 CH3 OH HO HO 2 2 Isoprenaline HCL Orciprenaline sulfate Salbutamol sulfate OH H HO CH3 N CH3 .H2SO4 CH3 OH 2 Terbutaline sulfate

  13. cAMP-PKA pathway Gα gated channel cAMP gated channel PO4 gated channel Receptor Adenylyl cyclase C C R R P cAMP C C R R P ATP cAMP g a ADP b cAMP cAMP R C cAMP cAMP ATP GTP a a cAMP cAMP R C CREB cAMP cAMP GTP GTP P Activated PKA CREB Inactive PKA P Gene expression CREB CRE Nucleus cAMP Response Element

  14. Primary Action of Epinephrinein a LiverCell Acetylcholine Epinephrine Stress signal Fuel for „fight or flight” Receptor P P P P P Glucose GlucogenSynthase AdenylateCyclase Glucose-6-Phosphatase g ATP cAMP as Glucose-6-P Glucose-1-P Glycogen b Fructose-2,6- bisphosphatase GDP Fructose-1,6- bisphosphatase PFK-1 Glucogen Phosphorylase Fructose-2,6-bisP Fructose-6-P Phosphorylase Kinase A Fructose-1,6-bisP Protein Kinase A PEP PyrKinase Pyruvate

  15. Glucagonsignaling Glucose low in blood PANCREAS Glucagon (Epinephrine) Receptor P P P P Glucose GlycogenSynthase AdenylateCyclase Glucose-6-Phosphatase g ATP cAMP as Glucose-6-P Glucose-1-P Glycogen b Fructose-2,6- bisphosphatase GDP Fructose-1,6- bisphosphatase PFK-1 Glycogen Phosphorylase Fructose-2,6-bisP Fructose-6-P Fructose-1,6-bisP Protein Kinase A PEP PyrKinase Pyruvate

  16. Serotonin receptor • Serotonin receptor → G-protein →adenylylcyclase→ ATP →cAMP→ PKA →cAMPResponseElement (CRE) →Geneexpression

  17. Types of serotonin receptor

  18. Receptor desensitization Desensitized receptor Activated receptor Arrestin ATP ADP GRK G-protein linked receptor kinase P P P P P P

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