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1 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 /1/A
2 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 /1/A Tímea Berki and Ferenc Boldizsár Signal transduction EXTRACELLULAR RECEPTORS ION CHANNELS
3 Scheme of the signal transduction of cell surface receptors Ligand Receptor Intracellular signaling Gene expression Biological response
4 Receptor families Extracellular receptors: hidrophylic ligands eg. peptide, protein hormones Ion-channel receptors 7-transmembrane-spanning receptors (7TM) Catalytic receptors: intrinsic enzyme activity Non-catalytic receptors: use cytoplasmic tyrosine kinases Intracellular receptors: lipophilic hormones eg. steroids, thyroxin
5 Extracellular receptor types ION-CHANNEL-LINKED RECEPTORS Ions Plasma membrane Signal molecule Cytoplasm G-PROTEIN-LINKED RECEPTORS Signal molecule a b g Enzyme a b g Enzyme a Enzyme GDP GTP GTP G-protein Activated G-protein b g Activated enzyme ENZYME-LINKED RECEPTORS Dimer of signal molecule Signal molecule Inactive catalytic domain Active catalytic domain Enzyme Activated enzyme
6 Receptors Receptors Ionotropic (ion-channel linked) GABA A, GABA C, iglu Glycine, Serotonin, Nicotinic Ach, P2X Metabotropic (use second messengers) GABA B, mglu, Adrenaline, Noradrenaline, Glucagon, FSH, LH, TSH, ADH, parathormone, growth-factors, cytokines
7 More receptors using the same second messenger system ACTH LH FSH Secretin Adrenaline Glucagon Adenylyl cyclase ATP camp
8 Receptor - ligand interaction Receptor properties Ligand binds in the core region of the 7 transmembrane helices Short peptide ligands bind partially in the core region and to the external loops Ligands make several contacts with the N- terminal segment and the external loops Induce an extensive reorganization of an extended N-terminal segment Proteinase activated receptors Ligands 11-cis-retinal (in rhodopsin) Acetylcholine Catecholamines Biogenic amines (histamine, serotomine, etc.) Nucleosides and nucleotides Leukotrienes, prostaglandins, prostacyclins, Thromboxanes Peptide hormones (ACTH, glucagon, growth hormone) Parathyroid hormone, calcitonin Hypothalamic glycoprotein releasing factors (TRH, GnRH) Metabotropic receptors for neurotransmitters (such as GABA and glutamate) Ca 2+ -sensing receptors, for example on parathyroid cells, thyroidal C-cells (which secrete calcitonin) and on the renal juxtaglomerular apparatus Receptors for thrombin amd thrypsin
9 Functional groups of ligands Inverse agonists Partial agonists and antagonists Agonists r R Inactive state Active state r R r R
10 Ionotropic receptors (ligand-gated ion channels) Ions Plasma membrane Ligand Cytoplasm Ligand gated ion channel
11 Ion channel receptors Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit e.g., Acetylcholin (Ach) Nicotinic R Na + channel e.g., GABA A, GABA C, Glycine Cl - channels (inhibitory role in CNS) Glutamate-activated cationic channels: (excitatory role in CNS), tetrameric stucture, 3 TM regions/subunit e.g., iglu ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit e.g., P2X purinoreceptor
12 Nicotinic Ach receptor FRONT TOP
13 Nicotinic Ach receptor Pore formed from 5 subunits: 2a, b, g, d Opening: the 2a units are distorted Desensitization: in the open conformation the b, g, d subunits become phosphorylated by Protein kinase A and C
14 The axon terminal Axon of motor neuron Axon terminal 1 Ca 2+ 2 Voltage-gated Ca 2+ channel Terminal button Vesicle of acethylcholine Voltage-gated Na + channel Neurotransmitter-gated channel 3 5 K Na + Motor end plate 7 Acetylcholine Acetylcholinesterase Muscle fiber ~4x10 7 nicotinic Ach Rs / end plate
15 Electric organs in animals Marine ray Torpedo Freshwater electric eel Electrophorus 2x10 11 nicotinic Ach receptors/end plate!
16 Blocking the neuromuscular transmission TÁMOP /1/A a-bungarotoxin: Snake venom (Bungarus multicinctus) Binds to the N-Ach receptor and inactivates Curare (tubocurarin): In South American plants Strychnos toxifera and Chondrodendron tomentosum Indians use as arrow poison Curare binds to the same place on the N-Ach receptor than Achetylcholin BUT channel doesn t open Causes paralysis of breathing muscles Used as muscle relaxant in anaesthesia Antidote: Acetylcholinesterase inhibitors
17 Acetylcholinesterase (AchE) Quick removal of Ach from the synaptic space Ach choline+acetyl Reversible inhibitors: therapeutic use (myasthenia, glaucoma, Alzheimer s) Irreversble inhibitors: chemical weapons and pesticides e.g. organophosphates Ach AchE
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