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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signal transduction G-PROTEIN-LINKED RECEPTORS TÁMOP-4.1.2-08/1/A-2009-0011 Nomenclature • • • • • • G-protein-coupled receptors (GPCRs) Seven-transmembrane domain receptors 7-TM receptors Heptahelical receptors Serpentine receptor G protein-linked receptors (GPLR) TÁMOP-4.1.2-08/1/A-2009-0011 7-transmembrane-spanning receptors (7-TM) N N-Glycosylation (Receptor folding, trafficking) EL1 EL2 EL3 Extracellular loops (EL1-3) Plasma membrane Interaction surface Ligand-binding TM 1 Gα C-terminal tail Gα -binding TM 2 TM 3 TM 4 TM 5 TM 6 Other Gα surfaces TM 7 Transmembrane helix (TM1-7) Helix 8 (Gβ-binding) Intracellular loops (IL1-3) PKC phosphorylation (Desensitization) IL1 E/DRY Motif (Receptor activity and protein-protein interactions) IL2 IL3 Palmitoylation (Lipid raft localization) C PKC phosphorylation (Desensitization) GRK phosphorylation (Desensitization) TÁMOP-4.1.2-08/1/A-2009-0011 GPCR TÁMOP-4.1.2-08/1/A-2009-0011 Structure of 7-TM receptors Inactive GPCR Active GPCR Side perspective Agonist N N EL 3 EL2 Intracellular loops EL1 TM 5 TM 7 TM 6 TM 1 TM 3 TM 2 C TM 1 TM 4 Extracellular loops TM 6 TM 7 TM 5 C TM 3 TM 2 IL3 TM 4 Gα Ga C-terminal tail of Ga IL 1 IL2 Intracellular persective Non-covalent bond C C N N EL3 EL3 IL3 TM 7 TM 6 TM 1 IL1 TM 2 TM 5 TM 3 EL1 IL2 TM 4 TM 6 TM 7 EL2 Ga-binding surface TM 1 IL1 Ga TM 2 TM 3 EL1 IL2 IL3 TM 5 TM 4 EL2 TÁMOP-4.1.2-08/1/A-2009-0011 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 TÁMOP-4.1.2-08/1/A-2009-0011 Activation of G-protein-coupled receptors (GPCR) Signal molecule G-protein coupled receptor (GPCR) a GDP b a b a GDP Inactive G-protein GTP GDP GTP Plasma membrane Cytoplasm a GTP b a b GTP Activated G-protein subunits b TÁMOP-4.1.2-08/1/A-2009-0011 G-proteins G-protein coupled receptor (GPCR) Plasma membrane a Cytoplasm b GDP a b GTP Gia ATP Gsa Gqa GTP GTP GTP Adenylyl cyclase Adenylyl cyclase cAMP ATP G12/13a GTP PLC cAMP PIP2 DAG IP3 Phospholipases Ion channels Ca2+ Activates Rho Ion channels PI3K Phospholipases Adenylyl cyclases Receptor kinases TÁMOP-4.1.2-08/1/A-2009-0011 G-protein heterotrimer TÁMOP-4.1.2-08/1/A-2009-0011 Catecholamine hormon synthesis +H N 3 CO2– +H +H N 3 CO2– 3N OH OH Tyrosine hydroxylase DOPA decarboxylase OH Dihydroxy phenilalanine (L-DOPA) Tyrosine +H N 3 Dopamine OH OH Dopamine H3C OH HO β-hydroxylase Phenethanolamine H2+ N OH HO N-methyltransferase OH Dopamine OH Epinephrine TÁMOP-4.1.2-08/1/A-2009-0011 Epinephrine and analogues OH H N HO CH3 H N .HCL HO HO OH OH NH2 CH3 .H2SO4 CH3 Tyramine HCL 2 Epinephrine (adrenaline) H N CH3 .HCL CH3 Pseudoephedrine HCL Ephedrine sulphate OH NH2 NH2 NH2 .H2SO4 .H2SO4 CH3 OH HO HO HO H N CH3 CH3 Isoprenaline HCL Dexamfetamine sulfate Amfetamine sulfate Phenylethanolamine sulfate OH 2 2 2 H N CH3 OH .H2SO4 CH3 .HCL HO OH HO 2 HO H N CH3 CH3 CH3 Salbutamol sulfate CH3 CH3 CH3 .H2SO4 OH 2 Terbutaline sulfate H N .H2SO4 2 Orciprenaline sulfate OH .H2SO4 CH3 TÁMOP-4.1.2-08/1/A-2009-0011 cAMP-PKA pathway Gα gated channel a b cAMP gated channel a a GTP GTP Adenylyl cyclase PO4 gated channel cAMP Receptor P P GTP ATP cAMP ADP R C R C Inactive PKA cAMP cAMP R cAMP R cAMP ATP cAMP cAMP R C C CREB C C cAMP R cAMP Activated PKA P CREB CRE cAMP Response Element P CREB Gene expression Nucleus TÁMOP-4.1.2-08/1/A-2009-0011 Primary Action of Epinephrine in a Liver Cell Acetylcholine Fuel for „fight or flight” Stress signal Epinephrine Receptor as P Glucose GDP Adenylate Cyclase ATP b Glucogen Synthase Glucose-6Phosphatase cAMP Glucose-6-P P Glucose-1-P Glycogen Fructose-2,6bisphosphatase Fructose-2,6-bisP Glucogen Phosphorylas e Fructose-6-P Fructose-1,6bisphosphatase P PFK-1 Fructose-1,6bisP P Protein Kinase A PEP P Pyr Kinase Pyruvate Phosphorylas e Kinase A TÁMOP-4.1.2-08/1/A-2009-0011 Glucagon signaling Glucagon (Epinephrine) Receptor as P Glucose GDP Adenylate Cyclase ATP b Glucose low in blood PANCREAS Glycogen Synthase Glucose-6Phosphatase cAMP Glucose-6-P P Glucose-1-P Glycogen Fructose-2,6bisphosphatase Fructose-2,6bisP Glycogen Phosphorylas e Fructose-6-P Fructose-1,6bisphosphatase PFK-1 Fructose-1,6bisP Protein Kinase A PEP P Pyr Kinase Pyruvate P TÁMOP-4.1.2-08/1/A-2009-0011 Serotonin receptor Serotonin receptor → G-protein → adenylyl cyclase → ATP → cAMP → PKA → cAMP Response Element (CRE) → Gene expression TÁMOP-4.1.2-08/1/A-2009-0011 Types of serotonin receptor Family Mechanism Potential 5-HT1 Decreasing cellular levels of cAMP Inhibitory 5-HT2 Increasing cellular levels of IP3 and DAG Excitatory 5-HT3 Depolarizing plasma membrane Excitatory 5-HT4 Increasing cellular levels of cAMP Excitatory 5-HT5 Decreasing cellular levels of cAMP Inhibitory 5-HT6 Increasing cellular levels of cAMP Excitatory 5-HT7 Increasing cellular levels of cAMP Excitatory TÁMOP-4.1.2-08/1/A-2009-0011 Receptor desensitization Desensitized receptor Activated receptor P P P P P P Arrestin ATP ADP GRK G-protein linked receptor kinase
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