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Signaling in the nervous system

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Signaling in the nervous system

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Signaling in the nervous system

  3. Synapsebetweentwoneurons-neurotransmission Presynaptic neuron (axonterminal) Synapticvesicles NT transporter Voltage-gatedsodiumchannel + Neurotransmittermolecule Ligand-gated ion channel (directexcitationorinhibition) Postsynaptic neuron GPCR (modulatory) +

  4. Mechanism of neurotransmission • Synapticvesiclescontain a neurotransmitter(NT) and releaseitwhentheirmembranesfusewiththeoutercellmembrane. • Neurotransmittermoleculescrossthesynapticcleft and bindtoreceptorsknownasligand-gated ion channels(LGICs) and G-protein–coupledreceptors(GPCRs) onthepostsynaptic neuron. • GPCRsonthepresynapticneuron’saxonterminalalterthefunction of voltage-gated ion channels and modulateneurotransmitterrelease. • Neurotransmittertransportersremoveneurotransmittermoleculesfromthesynapticcleftsothattheycan be repackagedintovesicles

  5. Receptors Receptors Ionotropic (ion-channel linked) Metabotropic (use second messengers) • GABAA, GABAC, iGlu • Glycine, • Serotonin, • Nicotinic Ach, • P2X • GABAB, mGlu, Adrenaline, Noradrenaline, Glucagon, FSH, LH, TSH, ADH, parathormone, • growth-factors, cytokines

  6. Receptor - ligandinteraction

  7. Ion channel receptors • 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) • Glutamate-activated cationic channels: (excitatory role in CNS),tetramericstucture, 3 TM regions/subunit • iGlu • ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit • P2X purinoreceptor

  8. 7-transmembrane-spanning receptors(7-TM) • Class A: Rhodopsin-like • Class B: Secretin family • Class C: Glutamate and GABA (metabotropic) • Frizzled • Adhesion family

  9. 7-TM ligands • Class A • Prostaglandins • Thromboxane • Serotonine • Dopamine • Histamine • Catecholamines • Ach (M) • Rhodopsin • Melatonin • Chemokines • Bradykinin • Somatostatin • Opioid • vasopressin • Class B • Glucagon • GnRH • PTH • CRH • Class C • Glutamate • GABA • Sweet tastes • Secretin • Frizzled • Wnt • Hedgehog • Bitter tastes • Adhesion • Chondroitin-sulfate

  10. 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

  11. Neurotransmission Neurotransmitter Ions g a Plasmamembrane Ion channel b Cytoplasm Neurotransmitter Receptor Plasma membrane Cytoplasm Effector protein Intracellular messengers a GTP GTP G-protein is activated G-protein subunits or intracellular messengers modulate ion channels

  12. Acetylcholine Nicotinicacetylcholine receptor (nAChR) O H3C CH3 NH2 One subunit of nAChR N Ligandbinding site O H3C CH3 Acetylcholine COOH Muscarinicacetylcholine receptor (mAChR) Fourhydrophobic transmembrane domain (TM1-4) Acetylcholine Extracellular TM 2 TM 4 TM 6 TM 1 TM 3 TM 5 TM 7 Extracellular TM 1 TM 2 TM 3 TM 4 M1, M3, M5 M2, M4 Cytoplasmic TM 2 TM 4 TM 6 TM 1 TM 3 TM 5 TM 7 Fiveassembledsubunits (2×+ 3×) of nAChR Ions pass through the pore Gq/11 Gi/0 Cytoplasmic Binding site for neurotransmitter ↑ [Ca2+] ↓ Adenylyl cyclase Extracellular   ↑ MAP kinases ↑ MAP kinases ↑ PLC ↑ GIRK channels Cytoplasmic ↓ M current ↓ Voltage-operated Ca2+ channels Change in intracellular ion contrentration

  13. Adrenergicreceptors Adrenalin, Noradrenalin Receptor 1 2  Gq Gi Gs Adenylylcyclase Phospholipase C Adenylylcyclase ATP cAMP PIP2 DAG ATP cAMP IP3 Ca2+ Ca2+ Smooth muscle relaxation Heartmusclecontraction Smoothmusclerelaxation Glycogenolysis Inhibition of transmitter release Smoothmusclecontraction

  14. Blocking the neuromuscular transmission • a-Bungarotoxin: • Snake venom (Bungarusmulticinctus) • Binds to the N-Ach receptor and inactivates • Curare (tubocurarin): • In South American plantsStrychnostoxiferaand Chondrodendrontomentosum • Indiansuseasarrow 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

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