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Neuromodulation in Neurotransmission: Receptor Interactions and Signaling Pathways

Explore the intricacies of synaptic transmission and receptor interactions in the nervous system, delving into mechanisms and novel challenges of the European Union. Study materials from medical biotechnology programs at the Universities of Pécs and Debrecen.

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Neuromodulation in Neurotransmission: Receptor Interactions and Signaling Pathways

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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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