8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology BASICS OF NEUROBIOLOGY IONOTROPIC RECEPTORS www.itk.ppke.hu Neurobiológia alapjai (Ionotrop receptorok) ZSOLT LIPOSITS Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu TRANSMITTER RECEPTORS WITH THE EXCEPTION OF STEROID SIGNALS AND UNCONVENTIONAL GAS TRANSMIT-TERS (NO, CO), REGULAR NEUROMESSENGERS CAN NOT DIFFUSE THROUGH THE CELL MEMBRANE THEIR EFFECTS ARE MEDIATED BY RECEPTORS THAT ARE EMBEDDED INTO THE POST-SYNAPTIC MEMBRANE RECEPTORS ARE COMPLEX PROTEINS THAT SHOW HIGH-AFFINITY BINDING FOR TRANSMITTER LIGANDS LIGAND BINDING ALTERS THE CONFORMATION OF THE RECEPTOR THAT EVOKES POSTSYNAPTIC RESPONSES THE RESPONSE DEPENDS ON THE AMOUNT OF THE TRANSMITTER, THE NUMBER AND STATE OF THE RECEPTORS TRANSMITTER RECEPTORS BELONG TO TWO CATEGORIES: IONOTROPIC RECEPTORS METABOTROPIC RECEPTORS Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu IONOTROPIC RECEPTORS FORM PORES, SPECIFIC ION CHANNELS IN THE MEMBRANE THAT ALLOW THE PASSAGE OF IONS UPON ACTIVATION. THEY PERFORM AS LIGAND-GATED ION CHANNELS METABOTROPIC RECEPTORS ARE COUPLED TO GTP-BINDING PROTEINS (G PROTEINS) VIA THEIR INTRACELLULAR DOMAINS. G PROTEIN ACTIVATION EVOKES SECONDARY RESPONSES IN THE CELL THAT ALTER THEIR METABOLISM. SYNONYM: G PROTEIN-COUPLED RECEPTORS (GPCRs) TRANSMITTER RECEPTORS IONOTROPIC RECEPTOR INTRACELLULAR MESSENGERS LIGAND IONS IONS METABOTROPIC RECEPTOR CELLULAR RESPONSE G PROTEIN Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu IONOTROPIC RECEPTORS IONOTROPIC RECEPTORS BY GATING ION CHANNELS CONTRIBUTE TO FAST POST-SYNAPTIC RESPONSES WITH REGARDS TO THE POSTSYNAPTIC EFFECT, THEY ARE EXCITATORY ORINHIBITORY IN NATURE IONOTROPIC RECEPTOR FAMILIES COMPRISE THE FOLLOWING RECEPTORS: NICOTINIC ACETYLCHOLINE RECEPTOR (nAChR) GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) GLYCINE RECEPTOR SEROTONIN RECEPTOR (5-HT3SUBCLASS) GLUTAMATE RECEPTORS NMDA RECEPTOR AMPA RECEPTOR KAINATE RECEPTOR GABA A RECEPTOR COURTESY OF LUNDBECK INSTITUTE, DENMARK Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu NICOTINICACETYLCHOLINE RECEPTOR ATTRIBUTE DESCRIPTION NAME NICOTINICACETYLCHOLINE RECEPTOR SUPERFAMILY NICOTINIC ACETYLCHOLINE RECEPTOR STRUCTURE PENTAMERIC, HOMO-OR HETEROMERIC VARIANTS SUBUNITS .1-10,ß1-4,., ., . EXPRESSION TYPES MUSCLE HETEROMERIC (.1)2ß1.., BRAIN HETEROMERIC (.4)2(ß2)3, BRAIN, GANGLION HOMOMERIC (.7)5, GANGLION HETEROMERIC (.3)2(ß4)3 LIGAND BINDING EXTRACELLULAR DOMAIN NEAR TO N TERMINUS, AT SUBUNIT INTERFACES BASIC ROLE(S) OPENS PORES FOR SODIUM ION INFLOW AND POTASSIUM ION OUTFLOW, MUSCLE CONTRACTION, EPSP AGONISTS NICOTINE, CHOLINE, EPIBATIDINE ANTAGONISTS GANGLIONIC: HEXAMETHONIUM, MUSCLE: ATRACURIUM, SUCCINYLCHOLINE, BRAIN; 18-METHOXYCORONARIDINE FUNCTIONAL ROLES EXECUTION OF MOVEMENT AND AUTONOMIC FUNCTIONS, MODULATION OF CNSNETWORKS VIA PRE-AND POSTSYNAPTIC REGULATION DISEASES MYASTHENIA GRAVIS, CONGENITAL MYASTHENIC DISEASES, TOBACCO ADDICTION Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu A B GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) ATTRIBUTE DESCRIPTION NAME GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) SUPERFAMILY NICOTINIC ACETYLCHOLINE RECEPTOR STRUCTURE PENTAMERIC SUBUNITS ., ß, ., ., ., ., ., ISOFORMS: .1-6, ß1-ß3, .1-.3, .1-.3. EXPRESSION TYPES MORE THAN 100 SUBTYPES LIGAND BINDING GABA AGONIST AND ANTAGONIST BINDING SITE, BENZODIAZEPINE SITE, STEROID SITE, BARBITURATE SITE, PICROTOXIN SITE BASIC ROLE(S) REGULATES CHLORIDE CHANNEL, IPSP AGONISTS MUSCIMOL, BACLOFEN, ETHANOL, BARBITURATES, BENZODIAZEPINES ANTAGONISTS BICUCULINE FUNCTIONAL ROLES AGONISTS EXERT ANXIOLYTIC, ANTICONVULSANT, AMNESIC, SEDATIVE, HYPNOTIC AND MUSCLE RELAXANT EFFECTS DISEASES EPILEPSY, ANXIETY Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu GLYCINE RECEPTOR ATTRIBUTE DESCRIPTION NAME GLYCINE RECEPTOR SUPERFAMILY NICOTINIC ACETYLCHOLINE RECEPTOR STRUCTURE PENTAMERIC SUBUNITS 5 SUBUNITS EXPRESSION TYPES (.1)3ß2 or (.1) 4ß LIGAND BINDING GABA AGONIST AND ANTAGONIST BINDING SITE, BENZODIAZEPINE SITE, STEROID SITE, BARBITURATE SITE, PICROTOXIN SITE BASIC ROLE(S) REGULATES CHLORIDE CHANNEL, IPSP AGONISTS SERINE, TAURINE, ANTAGONISTS STRYCHNINE, CAFFEINE FUNCTIONAL ROLES DOMINANT INHIBITORY NEUROTRANSMITTER IN THE SPINAL CORD AND BRAINSTEM DISEASES HYPEREKPLEXIA, STIFFNESS Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu SEROTONIN RECEPTOR (5-HT3SUBCLASS) ATTRIBUTE DESCRIPTION NAME SEROTONIN RECEPTOR (5-HT3SUBCLASS) SUPERFAMILY NICOTINIC ACETYLCHOLINE RECEPTOR STRUCTURE PENTAMERIC, HOMOMERIC OR HETEROMERIC FORMATIONS SUBUNITS A-E EXPRESSION TYPES 5-HT3AAND5-HT3BSUBUNITS IN CNS LIGAND BINDING AT THE INTERFACE OF TWO ADJACENT SUBUNITS BASIC ROLE(S) OPENS PORES FOR SODIUM ION INFLOW AND POTASSIUM ION OUTFLOW, EPSP AGONISTS BENZYLPIPERAZINE, QUIPAZINE ANTAGONISTS CARBAZOLE, INDAZOLES, INDOLES FUNCTIONAL ROLES ROLE IN ADDICTION, ANXIETY, EMESIS, GI MOTILITY, NAUSEA DISEASES ----------------------------------- Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu GLUTAMATE RECEPTOR-NMDA TYPE ATTRIBUTE DESCRIPTION NAME NMDA (N-methyl-D-aspartic acid) RECEPTOR SUPERFAMILY GLUTAMATE RECEPTOR STRUCTURE HETEROMERIC ASSEMBLIES MADE UP FROM NR1 SUBUNITS TOGETHER WITH AT LEAST ONE TYPE OF NR2 SUBUNIT SUBUNITS NR1, NR2, NR3 SUBFAMILIES EXPRESSION TYPES NR1: 8 ISOFORMS, NR2A-2D, NR3A-B (FOR SPLICE VARIANTS SEE TEXTBOOKS) LIGANDS IMPORTANT BINDING SITES FOR: NMDA, ASPARTATE, GLUTAMATE, GLYCINE, D-SERINE, POLYAMINE, Zn2+, Mg2+, H+ BASIC ROLE(S) NON SPECIFIC CATION CHANNEL ALLOWING CALCIUM, SODIUM AND POTASSIUM PASSAGE. FEATURES: LOW KINETICS, HIGH Ca2+ PERMEABILITY, VOLTAGE-DEPENDENT BLOCK BY Mg2+, GLYCINE CO-ACTIVATOR, POLYAMINE ACTIVATION, Zn2+INHIBITION AGONISTS GLUTAMATE, ASPARTATE, GLYCINE, D-SERINE ANTAGONISTS AMANTADINE, KETAMINE, PHENCYCLIDINE FUNCTIONAL ROLES LONG TERM POTENTIATION, SYNAPTIC PLASTICITY DISEASES EXCITOTOXICITY Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu SCHEME OF BINDING SITES OF NMDA RECEPTOR NMDA1.gif Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu AMPA RECEPTOR ATTRIBUTE DESCRIPTION NAME AMPA (.-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID ) RECEPTOR SUPERFAMILY GLUTAMATE RECEPTOR STRUCTURE HETEROTETRAMERIC SUBUNITS GluR1-GluR4 EXPRESSION TYPES (GluR1)2(GluR2)2 LIGAND BINDING EACH SUBUNIT HAS AN AGONIST BINDING SITE. THE RECEPTOR OPENS ANDCLOSES FAST, GATED BY SODIUM BASIC ROLE(S) MEDIATE MOST EXCITATORY ACTIONS IN THE CNS, FAST KINETICS, LOW CALCIUM PERMEABILITY. EPSP AGONISTS AMPA, DOMOIC ACID ANTAGONISTS GYKI53655, KYNURENIC ACID FUNCTIONAL ROLES SYNAPTIC TRANSMISSION, SYNAPTIC PLASTICITY DISEASES MOTOR NEURON DISEASE (AMYOTROPHIC LATERAL SCLEROSIS; ALS Basics of Neurobiology: Ionotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu KAINATE RECEPTOR ATTRIBUTE DESCRIPTION NAME KAINATE RECEPTOR SUPERFAMILY GLUTAMATE RECEPTOR STRUCTURE TETRAMERIC SUBUNITS GluR5-GluR7, KA1-KA2 EXPRESSION TYPES SUBUNITS FORM HOMO-AND HETERODIMERS LIGAND BINDING POCKET AT GluR6 BASIC ROLE(S) EXCITATORY AT POSTSYNAPTIC SITES, INHIBITORY AT PRESYNAPTIC LOCI. PORES ARE PERMEABLE FOR SODIUM AND POTASSIUM. KEPT OPEN SHORTER THAN AMPA RECEPTOR PORES AGONISTS SYM 2081, KAINIC ACID, DOMOIC ACID ANTAGONISTS NS102, KYNURENIC ACID FUNCTIONAL ROLES FUNCTION-DEPENDENT SYNAPTIC PLASTICITY DISEASES EPILEPSY