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 METABOTROPIC RECEPTORS www.itk.ppke.hu Neurobiológia alapjai (Metabotrop receptorok) ZSOLT LIPOSITS Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu CHARACTERISTICS OF METABOTROPICRECEPTORS SYNONYM FOR METABOTROPIC RECEPTOR IS G PROTEIN-COUPLED RECEPTOR THE BINDING OF THE LIGAND TO THE RECEPTOR RESULTS IN G PROTEIN ACTIVATION THAT TRIGGERS DOWNSTREAM EFFECTORS, MAINLY ENZYMES AND ION CHANNELS THE G PROTEIN-COUPLED RECEPTOR FAMILY HAS MORE THAN 1000 MEMBERS THE RESPONSE EVOKED VIA METABOTROPIC RECEPTORS HAS A SLOWER ONSET AND LONGER DURATION ( FROM 0.1 s TO HOURS). CERTAIN CLASSIC TRANSMITTERS UTILIZE BOTH THE FAST IONOTROPIC (RESPONSE TIME IS IN MILLISECONDS) AND THE SLOWER METABOTROPIC RECEPTORS FOR COMMUNICATION. PEPTIDES USE G PROTEIN-COUPLED RECEPTORS EXCLUSIVELY THE RECEPTORS BELONG TO SUBFAMILIES LIKE: METABOTROPIC GLUTAMATE TYPE RHODOPSIN-BETA ADRENERGIC TYPE SECRETIN-VIP TYPE Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu THE RECEPTOR POSSESSES 7 TRANSMEMBRANE DOMAINS LIGANDS COMPRISE LIGHT-SENSITIVE COMPOUNDS, ODORS, PHEROMONES, HORMONES, NEUROTRANSMITTERS, PEPTIDES AND LARGER PROTEINS THE ACTIVATED GPCR CAN TURN ON AN ASSOCIATED G-PRO- TEIN BY EXCHANGING ITS BOUND GDP FOR A GTP THE G PROTEIN HAS ALPHA, BETA AND GAMMA SUBUNITS. THE ALPHA SUBUNIT TOGETHER WITH THE BOUND GTP DISSOCIATES AND AFFECTS SECOND MESSENGERS GPCRs UTILIZE cAMP AND PHOSPHATIDYLINOSITOL SIGNAL TRANSDUCTION PATHWAYS CHARACTERISTICS OF METABOTROPICRECEPTORS GTP . ß a GTP LIGAND RECEPTOR . G PROTEIN GDP G PROTEIN ACTIVATION BY LIGAND BINDING OF THE RECEPTOR Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu SECOND MESSENGERS cAMP cGMP Ca2+Diacylglycerol IP3 THIRD MESSENGERS Protein phosphorylation RAPID MEDIATORY EFFECT Ion channel activation/inactivation SHORT TERM MODULATORY EFFECT General metabolism Transmitter synthesis/release Receptor sensitivity LONG TERM MODULATORY EFFECT Synthesis of receptors/channels Synaptogenesis Learning/memory METABOTROPIC SIGNAL TRANSDUCTION LIGAND RECEPTOR G PROTEIN ION CHANNEL MEMBRANE Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu . ß a . ß a GTP ADENYLYL CYCLASE LIGAND LIGAND RECEPTOR RECEPTOR MEMBRANE . . GTP STIMULATORY G PROTEIN INHIBITORY G PROTEIN ATP cAMP + - + PROTEIN KINASE A PROTEIN PHOSPHORYLATION STIMULATORY AND INHIBITORY G PROTEIN ACTIONS Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu MUSCARINIC ACETYLCHOLINE RECEPTOR ATTRIBUTE DESCRIPTION NAME MUSCARINIC ACETYLCHOLINE RECEPTOR STRUCTURE 7 TRANSMEMBRANE SUBTYPES FIVE SUBTYPES HAVE BEEN DETERMINED, NAMED M1-M5 EXPRESSION TYPES M1: CNS, EXOCRINE GLAND, M2: HEART, M3: SMOOTH MUSCLE OF BLOOD VESSELS. LUNG, M4, M5: CNS. PRE-AND POSTYNAPTIC RECEPTOR LOCATIONS IN THE BRAIN LIGAND BINDING HIGHER AFFINITY FOR MUSCARINE THAN NICOTINE BASIC ROLE(S) M1, M3, M5 COUPLE TO G PROTEINS THAT STIMULATE PHOSPHOLYPASEC M2, M4 COUPLE TO G PROTEINS THAT REGULATE POTASSIUM AND CALCIUM CHANNELS, INHIBIT ADENYLYL CYCLASE AGONISTS MUSCARINE, PILOCARPINE, BETANECHOL ANTAGONISTS ATROPINE, SCOPOLAMINE, PIRENZEPINE FUNCTIONAL ROLES REGULATION OF CNS NETWORKS AND AUTONOMIC NERVOUS SYSTEM DISEASES COGNITIVE DECLINE IN ALZHEIMER DISEASE DUE TO DIMINUTION OF ACETYLCHOLINE Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu METABOTROPIC GLUTAMATE RECEPTOR ATTRIBUTE DESCRIPTION NAME METABOTROPIC GLUTAMATE RECEPTOR STRUCTURE 7 TRANSMEMBRANE SUBTYPES EIGHT SUBTYPES DIVIDED INTO THREE GROUPS GROUP I: mGluR1and mGluR5 Group II: mGluR2 and mGluR3 GROUP III: mGluR4and mGluR6-8 EXPRESSION TYPES WIDE DISTRIBUTION IN THE BRAIN, PRE-AND POSTYNAPTIC RECEPTOR LOCATIONS, INHIBITORY, PRESYNAPTIC AUTORECEPTORS LIGAND BINDING AT EXTRACELLULAR N TERMINUS PART OF THE RECEPTOR BASIC ROLE(S) GROUP I: STIMULATION OF PHOSPHOLIPASE (PLC) C GROUP II: INHIBITION OF ADENYLYL CYCLASE GROUP III: INHIBITION OF ADENYLYL CYCLASE AGONISTS 2-CHLORO-5-HYDROXYPHENYLGLYCINE, (S)-3,5-DIHYDROXYPHENYLGLYCINE ANTAGONISTS 4-CARBOXYPHENYLGLYCINE, 1-AMINOINDAN-1,5-DICARBOXYLIC ACID FUNCTIONAL ROLES REGULATION OF CNS NETWORKS DISEASES mGluR1INVOLVED IN SYNAPTIC PLASTICITY, LTP AND LTD Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu METABOTROPIC GABA RECEPTOR ATTRIBUTE DESCRIPTION NAME METABOTROPIC GABA RECEPTOR (GABA B RECEPTOR) STRUCTURE 7 TRANSMEMBRANE, LARGE SIMILARITY WITH THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES TWO SPLICE VARIANTS ARE KNOWN (GABABR1, GABABR2) EXPRESSION TYPES WIDE DISTRIBUTION IN THE BRAIN, PRE-AND POSTYNAPTIC RECEPTOR LOCATIONS, LIGAND BINDING THE EXTRACELLULAR N TERMINUS PART OF THE RECEPTOR BASIC ROLE(S) ACTIVATION OF GABA B RECEPTORS LEADS TO AN INCREASE IN K+CONDUCTANCE, A DECREASE IN CA 2+ CONDUCTANCE AS WELL AS TO CHANGES IN THE LEVELS OF SECOND MESSENGERS (cAMP) AGONISTS BACLOFEN ANTAGONISTS SACLOFEN FUNCTIONAL ROLES REGULATION OF CNS NETWORKS DISEASES PAIN, EPILEPSY Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu METABOTROPIC SEROTONIN RECEPTOR ATTRIBUTE DESCRIPTION NAME METABOTROPIC SEROTONIN RECEPTOR STRUCTURE 7 TRANSMEMBRANE SUBTYPES 13 SUBTYPES, CATEGORIZED INTO 6 GROUPS (5HT1, 5HT2, 5HT4, 5HT5, 5HT6,5HT7) EXPRESSION TYPES WIDE DISTRIBUTION IN THE BRAIN LIGAND BINDING THE EXTRACELLULAR N DOMAIN OF THE RECEPTOR BASIC ROLE(S) INCREASING CELLULAR LEVELS OF cAMP: SUBTYPES 4,6,7 DECREASING CELLULAR LEVELS OF cAMP: SUBTYPES 1,5 INCREASING CELLULAR LEVELS OF IP3 AND DAG: SUBTYPE 2 AGONISTS LARGE SCALE OF SUBTYPE SPECIFIC AGONISTS ARE KNOWN ANTAGONISTS LARGE SCALE OF SUBTYPE SPECIFIC ANTAGONISTS ARE KNOWN FUNCTIONAL ROLES REGULATION OF CNS NETWORKS DISEASES ANXIETY, AGGRESSION, ADDICTION, MOOD, MEMORY, SLEEP Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu ACTION OF 5HT1A RECEPTOR ANTAGONIST COURTESY OF LUNDBECK INSTITUTE, DENMARK Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu DOPAMINERECEPTOR ATTRIBUTE DESCRIPTION NAME DOPAMINE RECEPTOR STRUCTURE 7 TRANSMEMBRANE SUBTYPES D1-LIKE AND D2-LIKE FAMILIES D1-LIKE,: D1, D5 RECEPTORS D2 LIKE: D2, D3, D4 RECEPTORS EXPRESSION TYPES WIDE DISTRIBUTION IN THE BRAIN. DOMINANT IN STRIATUM, N. ACCUMBENS, CORTEX LIGAND BINDING TRANSMEMBRANE SEGMENTS BASIC ROLE(S) D1-LIKE FAMILY ACTIVATES ADENYLYL CYCLASE D2-LIKE FAMILY INHIBITS ADENYLYL CYCLASE AGONISTS ROPINIROLE , PRAMIPEXOLE ANTAGONISTS CLOZAPINE, RISPERIDONE, OLANZAPINE, QUETIAPINE FUNCTIONAL ROLES REGULATION OF CNS NETWORKS, CONTROLLING MOVEMENT, MOOD, ADDICTION DISEASES PARKINSON DISEASE, SCHIZOPHRENIA, ATTENTION-DEFICIT HYPERACTIVITY DISORDER Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu DISTRIBUTION OF D1-D5 RECEPTORS IN THE HUMAN COURTESY OF LUNDBECK INSTITUTE, DENMARK Basics of Neurobiology: Metabotropic receptors 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 www.itk.ppke.hu ADRENERGIC RECEPTOR ATTRIBUTE DESCRIPTION NAME ADRENERGIC RECEPTOR. BINDS BOTH ADRENALINE AND NORADRENALINE STRUCTURE 7 TRANSMEMBRANE SUBTYPES 3 FAMILIES, ALPHA 1, ALPHA 2 AND BETA. SUBCLASSES IN EACH FAMILY EXPRESSION TYPES WIDE DISTRIBUTION IN THE BRAIN, HYPOTHALAMUS, CEREBRAL CORTEX IN THE CNS, ALPHA2A AND BETA 1 RECEPTORS ARE THE MAIN ADRENERGIC RECEPTORS ALPHA2A RECEPTORS PERFORM AS AUTORECEPTORS LIGAND BINDING THE EXTRACELLULAR DOMAIN OF THE RECEPTOR BASIC ROLE(S) ALPHA-2 ADRENERGIC RECEPTOR DECREASE CYCLIC AMP BETA ADRENERGIC RECEPTORS INCREASE CYCLIC AMP AGONISTS ISOPROTERENOL (SPECIFIC FOR BETA) ANTAGONISTS PROPRANOLOL (BETA), PHENTOLAMINE (ALPHA, WITH SOME BETA ACTION) FUNCTIONAL ROLES REGULATION OF CNS AND PNS FUNCTIONS DISEASES ANXIETY, POSTTRAUMATIC STRESS DISORDER (PTSD)