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 ION CHANNEL RECEPTORS TÁMOP-4.1.2-08/1/A-2009-0011 Ion channel receptors 1 Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit – Acetylcholin (Ach) Nicotinic R – Na+ channel - – GABAA, GABAC, Glycine – Cl channels (inhibitory role in CNS) 2 Glutamate-activated cationic channels: (excitatory role in CNS), tetrameric stucture, 3 TM regions/subunit – eg. iGlu 3 ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit – eg. P2X purinoreceptor TÁMOP-4.1.2-08/1/A-2009-0011 Cys-loop ion-channel receptors N Pore C C C N N N N C C TM TM TM TM 1 2 3 4 Receptor type GABAA GABAC Glycine g a b p2 p1 b a Subunit diversity a1-6, b1-3, g1-3, d,e,k, and q p1-3 a1-4, b TÁMOP-4.1.2-08/1/A-2009-0011 Vertebrate anionic Cys-loop receptors Type Class Protein name Gene Previous names a1 GABRA1 a2 GABRA2 a3 GABRA3 EJM, ECA4 alpha a4 GABRA4 a5 GABRA5 a6 GABRA6 b1 GABRB1 beta b2 GABRB2 ECA5 b3 GABRB3 g1 GABRG1 GABAA gamma g2 GABRG2 CAE2, ECA2, GEFSP3 g3 GABRG3 delta d GABRD epsilon e GABRE pi p GABRP theta q GABRQ GABRR rho r GABRR GABAC GABRR a1 GLRA1 a2 GLRA2 alpha STHE Glycine (GlyR) a3 GLRA3 a4 GLRA4 beta b GLRB TÁMOP-4.1.2-08/1/A-2009-0011 Vertebrate cationic Cys-loop receptors Type Class Protein name Gene Previous names 5-HT3A HTR3A 5-HT 5-HT3B HTR3B 3A 5-HT Serotonin 5-HT3C HTR3C 3B 5-HT3 5-HT (5-HT) 5-HT3D HTR3D 3C 5-HT 5-HT3E HTR3E 3D 5-HT 3E a1 CHRNA1 a2 CHRNA2 a3 CHRNA3 a4 CHRNA4 a5 CHRNA5 alpha ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS a6 CHRNA6 a7 CHRNA7 a8 CHRNA8 a9 CHRNA9 Nicotinic acetylcholine a10 CHRNA10 (nAChR) b1 CHRNB1 b2 CHRNB2 beta CMS2A, SCCMS, ACHRB, CHRNB, CMS1D, EFNL3, nAChRB2 b3 CHRNB3 b4 CHRNB4 gamma g CHRNG ACHRG delta d CHRND ACHRD, CMS2A, FCCMS, SCCMS epsilon e CHRNE ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS Zinc-activated ion ZAC ZACN ZAC1, L2m, LGICZ1 channel TÁMOP-4.1.2-08/1/A-2009-0011 Ionotropic glutamate receptors Type Class Protein name Gene Previous names GluA1 GRIA1 GLUA1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1 GluA2 GRIA2 GLU , GluR2, GluRB, GluR-B, GluR-K2, HBGR2 AMPA GluA1 A2 GluA3 GRIA3 GLUA3, GluR3, GluRC, GluR-D, GluR-K3 GluA4 GRIA4 GLUA4, GluR4, GluRD, GluR-D GluK1 GRIK1 GLUK5, GluR5, GluR-5, EAA3 GluK2 GRIK2 GLUK6, GluR6, GluR-6, EAA4, Kainate GluK GluK3 GRIK3 GLUK7, GluR7, GluR-7, EAA5, GluK4 GRIK4 GLUK1, KA1, KA-1, EAA1 GluK5 GRI5 GLUK2, KA2, KA-2, EAA2 GluN1 GRIN1 GluN NRL1A GRINL1A GLUN1, NMDA-R1, NR1, GluRz1 NRL1B GRINL1B GluN2A GRIN2A GLUN2A, NMDA-R2A, NR2A, GluRe1 NMDA GluN2B GRIN2B GLUN2B, NMDA-R2B, NR2B, GluRe2 GluN2C GRIN2C GLUN2C, NMDA-R2C, NR2C, GluRe3 GluN2D GRIN2D GLUN2D, NMDA-R2D, NR2D, GluRe4 GluN3A GRIN3A GLUN3A, NMDA-R3A, NMDAR-L, chi-1 GluN3B GRIN3B GLUN3B, NMDA-R3B GluD1 GRID1 ‘Orphan’ (GluD) GluRd1 GluD2 GRID2 TÁMOP-4.1.2-08/1/A-2009-0011 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 Top Front TÁMOP-4.1.2-08/1/A-2009-0011 Common neurotransmitters Neurotransmitter Action Receptor subtypes Acetylcholine (Ach) +/- Nicotinic, Muscarinic Norepinephrine (NE) + α1/2, β1/2/3 Dopamine +/- D1-D4 Serotonin (5-HT) +/- 5-HT1A etc. Glutamate (Glu) + NMDA, AMPA GABA - GABAA, GABAB Encephalins - μ, κ, δ TÁMOP-4.1.2-08/1/A-2009-0011 Synapse between two neurons - neurotransmission Presynaptic neuron (axon terminal) Synaptic vesicles NT transporter Voltage-gated sodium channel + Neurotransmitter molecule Ligand-gated ion channel (direct Postsynaptic neuron excitation or GPCR + inhibition) (modulatory) TÁMOP-4.1.2-08/1/A-2009-0011 Neurotransmission Ions Neurotransmitter Plasma membrane Cytoplasm Ion channel Neurotransmitter Receptor Plasma membrane Cytoplasm a g a b Effector Intracellular GTP GTP protein messengers G-protein is activated G-protein subunits or intracellular messengers modulate ion channels TÁMOP-4.1.2-08/1/A-2009-0011 Neurotransmitters Acetylcholine Acetylcholine (motor neurons) m/i Indolamines Serotonin (memory, emotion) m/i Monoamines Dopamine (motivation, addiction) m Catecholamines Norepinephrine/Noradrenaline (sympathetic NS) m Epinephrine m Glutamate (most prominent in CNS, excitatory) m/i GABA (30%-40% of CNS synapses, inhibitory) m/i Amino Acids Aspartate i Glycine (can be excit. or inhib. depending on Cl- conc.) * i Adenosine m Guanosine m Purines ATP i/m Others Endorphins Opioids Enkephalins Dynorphins Neuropeptides Substance P Non-opioids Neuropeptide Y m Others NO Soluble gases CO TÁMOP-4.1.2-08/1/A-2009-0011 Acetylcholine receptors Stage 1 Stage 2 Stage 3 Nicotinic muscle Nicotinic Junctional [(a1)2bed] Phenyltrimethyl-ammonium Nicotinic Embyonic [(a1) bgd] Elapid a-toxins, d-Tubocurarine 2 Nicotinic Neuronal a2 (a-toxin insensitive) Nicotinic Nicotinic Neuronal b2 Nicotine Nicotinic Neuronal a3 (a-toxin insensitive) d-Tubocurarine Nicotinic Neuronal b3 Nicotinic Neuronal a4 (a-toxin insensitive) Nicotinic neuronal (a+b) Nicotinic Neuronal b4 Dimethylphenyl-piperazinuim, Cystine Nicotinic Neuronal a5 (a-toxin insensitive) Trimethaphan Nicotinic Neuronal b5 Neuronal bungarotoxin Cholinergic Nicotinic Neuronal a5 (non-functional without a subunits) Acetylcholine Nicotinic Neuronal a6 (a-toxin insensitive) Nicotinic Neuronal a7 (a-toxin sensitive) Nicotinic Neuronal a8 (a-toxin sensitive) Nicotinic Neuronal a9 Muscarinic m1-M1 Pirenzepine Muscarinic m2-M2 Methoctramine Muscarinic Oxotremorine Muscarine, Pilocarpine Propyllbenzilylcholine mustard Muscarinic m4-M4 Himbacine Atropine Quinuclidinyl benzilate Muscarinic m3-M3 Hexahydro-siladifenidol Muscarinic m5-M5 TÁMOP-4.1.2-08/1/A-2009-0011 Acetylcholin-esterase (AchE): • Quick removal of Ach from the synaptic space • Ach → choline+acetyl • Reversible inhibitors: therapeutic use (myasthenia, glaucoma, Alzheimer’s) • Irreversible inhibitors: chemical weapons and pesticides eg. organophosphates Ach AchE .