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Extracellular receptors g-protein coupled 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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Extracellular receptors g-protein coupled 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 Extracellularreceptorsg-protein coupledreceptors

  3. 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

  4. 7-transmembrane-spanning receptors(7-TM) • Class A: Rhodopsin-like • Class B: Secretin family • Class C: Glutamate and GABA (metabotropic) • Frizzled • Adhesion family

  5. 7-transmembrane-spanning receptors(7-TM) Endogenousligand/Orphan (271) Class A (662) Olfactory/Pheromone (391) Class B (15) GPCR superfamily (791 genes) Class C (22) Others (92)

  6. 7-TM ligands

  7. Inactive 7-TM receptor N EL 3 EL2 EL1 Intracellularloops TM 7 TM 6 TM 1 TM 5 Sideperspective TM 3 TM 2 C TM 4 Helix8 IL3 Extracellularloops IL 1 IL2 TM 7 TM 6 TM 1 TM 5 TM 3 Intracellularperspective TM 2 TM 4 Non-covalent bond C N Helix8 EL3 IL3 Ga-binding surface IL1 EL2 EL1 IL2

  8. Active 7-TM receptor Agonist N TM 5 TM 6 TM 7 Sideperspective TM 1 TM 3 TM 2 C TM 4 Helix8 Gα Ga C-terminaltail of Ga C N EL3 Helix8 TM 6 TM 7 IL3 TM 1 TM 5 EL2 TM 3 IL1 Intracellularperspective Ga TM 2 TM 4 EL1 IL2

  9. 7-TM receptors bind to G-proteins(G-protein-coupled receptors, GPCR) Signalmolecule G-protein coupled receptor (GPCR) g g g a a a b b b Inactive G-protein GTP GDP GDP g a b GTP GDP GTP Plasmamembrane g b Cytoplasm a GTP Activated G-protein subunits

  10. G-proteins Stimulatory hormone Inhibitory hormone Adenylyl cyclase (+) (-) Rs Ri Gs Gi GTP GTP   Gs Gi β β GDP GDP ATP Phosphodiesterase cAMP 5’-AMP Protein kinase A Inactive Protein kinase A Active Protein Protein Cellularresponse OH P

  11. G-proteins G-protein coupled receptor (GPCR) Plasmamembrane Cytoplasm   β GDP G12/13  Gs Gq Gi  β GTP GTP GTP GTP GTP Ion channels PI3K Phospholipases Adenylyl cyclases Receptor kinases Adenylyl cyclase Adenylyl cyclase PLC PIP2 DAG ActivatesRho ATP cAMP ATP cAMP IP3 Phospholipases Ion channels Ca2+

  12. G-proteins • GTP-binding proteins • GTPase activity: they hydrolyse GTP to GDP • Inactive form: GDP-bound • Active form: GTP-bound • Heterotrimeric: a, b, g subunits • Monomeric: products of ras proto-oncogens • g subunit contains C terminal isoprenyl chains: anchoring in the plasma membrane

  13. G-protein signaling • 1Ga signaling • Gs: stimulate adenylyl-cyclase→cAMP↑ • Gi: inhibit adenylyl-cyclase→cAMP↓ • Gq: stimulate PLC • G12: Rho-GEF • 2Gb,g signaling • K+ and Ca2+ channels, PI3K isoforms

  14. GPCR regulation • PKA feedback phosphorylation • G-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 surface • Arrestin 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, Src

  15. Monomeric G-proteins (Ras family) • First found as transforming oncogenes: Harvey (H-Ras) and Kirsten (K-Ras) sarcoma viruses; Rat sarcoma • N-Ras found in human neuroblastoma • 189 AA • Anchored to the membrane through lipid chains • Mutations in the Ras family is found in 20-30% of all human tumors

  16. Ras regulation • Guanine-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→Inactivation

  17. Ras function – MAPK cascade • Signaling through growth factor receptors • Ras-Raf-MEK-ERK (Mitogen-activated protein kinase=MAPK cascade) • Increased activity (=“constitutively active Ras”) promotes tumor transformation • G-nucleotide exchange ↑ (point mutations) • GTPase activity ↓ (point mutations or lack of GAP)

  18. Ras-MAPK cascade Growthfactor/Hormone Receptor PTK Plasmamembrane RAS ActiveRAS Cytoplasm RAF Y Y SOS Y Y GRB2 Guaninenucleotide exchangefactor (GEF) MEK1/2 Y Y Adaptor ERK1/2 Elk-1 Sap1a Net Transcriptionalregulation

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