IONOTROPIC RECEPTORS
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1 BASICS OF NEUROBIOLOGY IONOTROPIC RECEPTORS ZSOLT LIPOSITS 1
2 NEURAL COMMUNICATION 2
3 Post-synaptic mechanisms Receptors-signal transduction-messengers 3
4 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: Ø Ø IONOTROPIC RECEPTORS METABOTROPIC RECEPTORS 4
5 TRANSMITTER RECEPTORS 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) IONOTROPIC RECEPTOR IONS LIGAND METABOTROPIC RECEPTOR IONS G PROTEIN INTRACELLULAR MESSENGERS CELLULAR RESPONSE 5
6 6
7 IONOTROPIC RECEPTORS IONOTROPIC RECEPTORS BY GATING ION CHANNELS CONTRIBUTE TO FAST POST- SYNAPTIC RESPONSES WITH REGARDS TO THE POSTSYNAPTIC EFFECT, THEY ARE EXCITATORY OR INHIBITORY IN NATURE IONOTROPIC RECEPTOR FAMILIES COMPRISE THE FOLLOWING RECEPTORS: q NICOTINIC ACETYLCHOLINE RECEPTOR (nachr) q GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) q GLYCINE RECEPTOR q SEROTONIN RECEPTOR (5-HT 3 SUBCLASS) q GLUTAMATE RECEPTORS ØNMDA RECEPTOR ØAMPA RECEPTOR ØKAINATE RECEPTOR GABA A RECEPTOR COURTESY OF LUNDBECK INSTITUTE, DENMARK 7
8 ION CHANNELS 8
9 Types of ion channels 9
10 Voltage-gated Na channel 10
11 Voltage-gated K channel 11
12 Patch-clamp method 12
13 Ligand-gated channel 13
14 Ligand-gated ion channels 14
15 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES DISEASES NICOTINIC ACETYLCHOLINE RECEPTOR NICOTINIC ACETYLCHOLINE RECEPTOR NICOTINIC ACETYLCHOLINE RECEPTOR DESCRIPTION PENTAMERIC, HOMO- OR HETEROMERIC VARIANTS a1-10,b1-4, g, d, e MUSCLE HETEROMERIC (a1) 2 b1de, BRAIN HETEROMERIC (a4) 2 (b2) 3, BRAIN, GANGLION HOMOMERIC (a7) 5, GANGLION HETEROMERIC (a3) 2 (b4) 3 EXTRACELLULAR DOMAIN NEAR TO N TERMINUS, AT SUBUNIT INTERFACES OPENS PORES FOR SODIUM ION INFLOW AND POTASSIUM ION OUTFLOW, MUSCLE CONTRACTION, EPSP NICOTINE, CHOLINE, EPIBATIDINE GANGLIONIC: HEXAMETHONIUM, MUSCLE: ATRACURIUM, SUCCINYLCHOLINE, BRAIN; 18- METHOXYCORONARIDINE EXECUTION OF MOVEMENT AND AUTONOMIC FUNCTIONS, MODULATION OF CNS NETWORKS VIA PRE- AND POSTSYNAPTIC REGULATION MYASTHENIA GRAVIS, CONGENITAL MYASTHENIC DISEASES, TOBACCO ADDICTION 15
16 Nicotinic acetylcholine receptor 16
17 17
18 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES SEROTONIN RECEPTOR (5-HT 3 SUBCLASS) DESCRIPTION SEROTONIN RECEPTOR (5-HT 3 SUBCLASS) NICOTINIC ACETYLCHOLINE RECEPTOR PENTAMERIC, HOMOMERIC OR HETEROMERIC FORMATIONS A-E 5-HT 3A AND 5-HT 3B SUBUNITS IN CNS LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES AT THE INTERFACE OF TWO ADJACENT SUBUNITS OPENS PORES FOR SODIUM ION INFLOW AND POTASSIUM ION OUTFLOW, EPSP BENZYLPIPERAZINE, QUIPAZINE CARBAZOLE, INDAZOLES, INDOLES ROLE IN ADDICTION, ANXIETY, EMESIS, GI MOTILITY, NAUSEA DISEASES
19 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES LIGANDS BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES DISEASES GLUTAMATE RECEPTOR-NMDA TYPE NMDA (N-methyl-D-aspartic acid) RECEPTOR GLUTAMATE RECEPTOR DESCRIPTION HETEROMERIC ASSEMBLIES MADE UP FROM NR1 SUBUNITS TOGETHER WITH AT LEAST ONE TYPE OF NR2 SUBUNIT NR1, NR2, NR3 SUBFAMILIES NR1: 8 ISOFORMS, NR2A-2D, NR3A-B (FOR SPLICE VARIANTS SEE TEXTBOOKS) IMPORTANT BINDING SITES FOR: NMDA, ASPARTATE, GLUTAMATE, GLYCINE, D-SERINE, POLYAMINE, Zn2 +, Mg2 +, H + NON SPECIFIC CATION CHANNEL ALLOWING CALCIUM, SODIUM AND POTASSIUM PASSAGE. FEATURES: LOW KINETICS, HIGH Ca 2+ PERMEABILITY, VOLTAGE-DEPENDENT BLOCK BY Mg2 +, GLYCINE CO-ACTIVATOR, POLYAMINE ACTIVATION, Zn2 + INHIBITION GLUTAMATE, ASPARTATE, GLYCINE, D-SERINE AMANTADINE, KETAMINE, PHENCYCLIDINE LONG TERM POTENTIATION, SYNAPTIC PLASTICITY EXCITOTOXICITY 19
20 NMDA receptor 20
21 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS AMPA RECEPTOR DESCRIPTION AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic ACID ) RECEPTOR GLUTAMATE RECEPTOR HETEROTETRAMERIC GluR1-GluR4 EXPRESSION TYPES (GluR1) 2 (GluR2) 2 LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES DISEASES EACH SUBUNIT HAS AN AGONIST BINDING SITE. THE RECEPTOR OPENS AND CLOSES FAST, GATED BY SODIUM MEDIATE MOST EXCITATORY ACTIONS IN THE CNS, FAST KINETICS, LOW CALCIUM PERMEABILITY. EPSP AMPA, DOMOIC ACID GYKI53655, KYNURENIC ACID SYNAPTIC TRANSMISSION, SYNAPTIC PLASTICITY MOTOR NEURON DISEASE (AMYOTROPHIC LATERAL SCLEROSIS; ALS 21
22 AMPA receptor Structure of a prototype a-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA) receptor subunit. The common transmembrane topology of all AMPA receptors is shown with individual features taken from glutamate receptor (GluR) subunit 1, GluR2 and GluR3. The glutamate binding site, the glutamine/arginine site and the flipflop cassette are common to all AMPA receptor subunits. The phosphorylation sites are specific to GluR1, the N-ethyl-maleimide sensitive factor (NSF) site is specific to GluR2, and the glutamate receptor interacting protein, AMPA receptor binding protein and protein interacting with Ckinase (GRIPABP Pick1) site is specific to GluR2 and GluR3. 22
23 AMPA and NMDA receptors in glutamatergic synapse 23
24 24
25 ampa_and_nmda.html 25
26 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES KAINATE RECEPTOR GLUTAMATE RECEPTOR TETRAMERIC GluR5-GluR7, KA1-KA2 KAINATE RECEPTOR DESCRIPTION SUBUNITS FORM HOMO- AND HETERODIMERS POCKET AT GluR6 EXCITATORY AT POSTSYNAPTIC SITES, INHIBITORY AT PRESYNAPTIC LOCI. PORES ARE PERMEABLE FOR SODIUM AND POTASSIUM. KEPT OPEN SHORTER THAN AMPA RECEPTOR PORES SYM 2081, KAINIC ACID, DOMOIC ACID NS102, KYNURENIC ACID FUNCTION-DEPENDENT SYNAPTIC PLASTICITY DISEASES EPILEPSY 26
27 ATTRIBUTE GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) A DESCRIPTION NAME B SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES DISEASES GAMMA-AMINOBUTYRIC ACID A RECEPTOR (GABA-A) NICOTINIC ACETYLCHOLINE RECEPTOR PENTAMERIC a, b, g, d, e, p, y, ISOFORMS: a1-6, b1-b3, g1-g3, r1-r3. MORE THAN 100 SUBTYPES GABA AGONIST AND ANTAGONIST BINDING SITE, BENZODIAZEPINE SITE, STEROID SITE, BARBITURATE SITE, PICROTOXIN SITE REGULATES CHLORIDE CHANNEL, IPSP MUSCIMOL, BACLOFEN, ETHANOL, BARBITURATES, BENZODIAZEPINES BICUCULINE AGONISTS EXERT ANXIOLYTIC, ANTICONVULSANT, AMNESIC, SEDATIVE, HYPNOTIC AND MUSCLE RELAXANT EFFECTS EPILEPSY, ANXIETY 27
28 GABA-A-R 28
29 Ionotropic GABA-A receptor animation 29
30 ATTRIBUTE NAME SUPERFAMILY STRUCTURE SUBUNITS EXPRESSION TYPES LIGAND BINDING BASIC ROLE(S) AGONISTS ANTAGONISTS FUNCTIONAL ROLES DISEASES GLYCINE RECEPTOR DESCRIPTION GLYCINE RECEPTOR NICOTINIC ACETYLCHOLINE RECEPTOR PENTAMERIC 5 SUBUNITS (α1) 3 β 2 or (α1) 4 β GLYCINE, TAURINE, SERINE REGULATES CHLORIDE CHANNEL, IPSP SERINE, TAURINE, STRYCHNINE, CAFFEINE DOMINANT INHIBITORY NEUROTRANSMITTER IN THE SPINAL CORD AND BRAINSTEM HYPEREKPLEXIA, STIFFNESS 30
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