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-4.1.2-08/1/A-2009-0011

2. SIGNALING IN THE NERVOUS SYSTEM Tímea Berki and Ferenc Boldizsár Signal transduction 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

3. TÁMOP-4.1.2-08/1/A-2009-0011 Presynaptic neuron (axon terminal) Postsynaptic neuron Neurotransmitter molecule NT transporter Synaptic vesicles Voltage- gated sodium channel GPCR (modulato ry) Ligand- gated ion channel (direct excitation or inhibition) + + Synapse between two neurons- neurotransmission

4. TÁMOP-4.1.2-08/1/A-2009-0011 Mechanism of neurotransmission neurotransmitterSynaptic vesicles contain a neurotransmitter (NT) and release it when their membranes fuse with the outer cell membrane. Neurotransmitter molecules cross the synaptic cleft and bind to receptors known as ligand-gated ion channels (LGICs) and G- protein–coupled receptors (GPCRs) on the postsynaptic neuron. GPCRs on the presynaptic neuron’s axon terminal alter the function of voltage-gated ion channels and modulate neurotransmitter release. Neurotransmitter transporters remove neurotransmitter molecules from the synaptic cleft so that they can be repackaged into vesicles

5. TÁMOP-4.1.2-08/1/A-2009-0011Receptors Ionotropic (ion-channel linked)Metabotropic (use second messengers) GABA A, GABA C, iGlu Glycine, Serotonin, Nicotinic Ach, P2X GABA B, mGlu, Adrenaline, Noradrenaline, Glucagon, FSH, LH, TSH, ADH, parathormone, growth-factors, cytokines Receptors

6. TÁMOP-4.1.2-08/1/A-2009-0011 Receptor - ligand interaction Receptor propertiesLigands Ligand binds in the core region of the 7 transmembrane helices 11-cis-retinal (in rhodopsin) Acetylcholine Catecholamines Biogenic amines (histamine, serotonine, etc.) Nucleosides and nucleotides Leukotrienes, prostaglandins, prostacyclins, Thromboxanes Short peptide ligands bind partially in the core region and to the external loops Peptide hormones (ACTH, glucagon, growth hormone) Parathyroid hormone, calcitonin Ligands make several contacts with the N- terminal segment and the external loops hypothalamic glycoprotein releasing factors (TRH, GnRH) Induce an extensive reorganization of an extended N-terminal segment 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 Proteinase activated receptorsReceptors for thrombin amd thrypsin

7. TÁMOP-4.1.2-08/1/A-2009-0011 Ion channel receptors Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit –Acetylcholin (Ach) Nicotinic R – Na + channel –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 –iGlu ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit –P2X purinoreceptor

8. TÁMOP-4.1.2-08/1/A-2009-0011 7-transmembrane-spanning receptors (7-TM) Class A: Rhodopsin-like Class B: Secretin family Class C: Glutamate and GABA (metabotropic) Frizzled Adhesion family

9. TÁMOP-4.1.2-08/1/A-2009-0011 7-TM ligands Class A Prostaglandin s Thromboxane Serotonine Dopamine Histamine Catecholamine s Ach (M) Rhodopsin Melatonin Chemokines Bradykinin Somatostatin Opioid vasopressin Class B Glucagon GnRH PTH CRH Class C Glutamate GABA Sweet tastes SecretinFrizzled Wnt Hedgehog Bitter tastesAdhesion Chondroitin- sulfate

10. TÁMOP-4.1.2-08/1/A-2009-0011 Nicotinic Ach receptor Pore formed from 5 subunits: 2 , , ,  Opening: the 2a units are distorted Desensitization: in the open conformation the , ,  subunits become phosphorylated by Protein kinase A and C

11. TÁMOP-4.1.2-08/1/A-2009-0011 Neurotransmission Ions GTP  Receptor G-protein is activated Effector protein Intracellular messengers G-protein subunits or intracellular messengers modulate ion channels Neurotransmitter GTP    Cytoplasm Plasma membrane Neurotransmitter Ion channel Cytoplasm Plasma membrane

12. TÁMOP-4.1.2-08/1/A-2009-0011 Acetylcholine  Ions pass through the pore Binding site for neurotransmitter Change in intracellular ion contrentration Five assembled subunits (2×  + 3×  ) of nAChR Extracellular Cytoplasmic COOH NH 2 TM 1 TM 2 TM 3 TM 4 Extracellular Cytoplasmic Ligand binding site Four hydrophobic transmembrane domain (TM1-4) One subunit of nAChR Nicotinic acetylcholine receptor (nAChR) O N O CH 3 H3CH3C H3CH3C Acetylcholine ↑ PLC  ↑ [Ca 2+ ] ↑ MAP kinases ↓ M current↓ Voltage-operated Ca 2+ channels ↓ Adenylyl cyclase ↑ MAP kinases ↑ GIRK channels Extracellular Cytoplasmic Muscarinic acetylcholine receptor (mAChR) Acetylcholine M1, M3, M5M2, M4 TM 1 TM 3 TM 5 TM 7 TM 2 TM 4 TM 6 Gq/1 1 Gi/0 TM 1 TM 3 TM 5 TM 7 TM 2 TM 4 TM 6

13. TÁMOP-4.1.2-08/1/A-2009-0011 Adrenergic receptors Receptor Gi 22 Inhibition of transmitter release Inhibition of transmitter release Ca 2+ Adenylyl cyclase ATPATPcAMPcAMP Smooth muscle relaxation Smooth muscle relaxation Gq 11 Smooth muscle contraction Ca 2+ Phospholipase C PIP 2 IP 3 DAG Gs  Heart muscle contraction Smooth muscle relaxation Glycogenolysis Heart muscle contraction Smooth muscle relaxation Glycogenolysis Adenylyl cyclase ATPATPcAMPcAMP Adrenalin, Noradrenalin

14. TÁMOP-4.1.2-08/1/A-2009-0011 Blocking the neuromuscular transmission 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