Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
SIGNALING IN THE NERVOUS SYSTEM
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
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 (modulator
y)
Ligand-gated ion channel
(direct excitation or inhibition)
+
+
Synapse between two neurons- neurotransmission
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Mechanism of neurotransmission• Synaptic 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
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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
Receptors
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Receptor - ligand interaction
Receptor properties Ligands
Ligand binds in the core region of the 7 transmembrane helices
11-cis-retinal (in rhodopsin)AcetylcholineCatecholaminesBiogenic amines (histamine, serotonine, etc.)Nucleosides and nucleotidesLeukotrienes, 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)Ca2+-sensing receptors, for example on parathyroid cells, thyroidal C-cells (which secrete calcitonin) and on the renal Juxtaglomerular apparatus
Proteinase activated receptors Receptors for thrombin amd thrypsin
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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), tetrameric stucture, 3 TM regions/subunit– iGlu
• ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit– P2X purinoreceptor
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7-transmembrane-spanning receptors (7-TM)• Class A: Rhodopsin-like• Class B: Secretin family• Class C: Glutamate and GABA (metabotropic)• Frizzled• Adhesion family
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7-TM ligandsClass AProstaglandinsThromboxaneSerotonineDopamineHistamineCatecholaminesAch (M)RhodopsinMelatoninChemokinesBradykininSomatostatinOpioidvasopressin
Class BGlucagonGnRHPTHCRH
Class CGlutamateGABASweet tastesSecretin
FrizzledWntHedgehogBitter tastes
AdhesionChondroitin-sulfate
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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
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NeurotransmissionIons
GTP
a
Receptor
G-protein isactivated
Effector protein
Intracellularmessengers
G-protein subunits or intracellularmessengers modulate ion channels
Neurotransmitter
GTP
gba
Cytoplasm
Plasma membrane
Neurotransmitter
Ion channel
Cytoplasm
Plasma membrane
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Acetylcholine
ba
Ions pass through the pore
Binding site forneurotransmitter
Change in intracellularion contrentration
Five assembled subunits(2×a + 3×b) of nAChR
Extracellular
Cytoplasmic
COOH
NH2
TM1
TM2
TM3
TM4
Extracellular
Cytoplasmic
Ligand binding site
Four hydrophobictransmembranedomain (TM1-4)
One subunit of nAChR
Nicotinic acetylcholine receptor (nAChR)
ON
OCH3
H3C
H3C
CH3Acetylcholine
↑ PLCb
↑ [Ca2+]↑ MAP kinases
↓ M current ↓ Voltage-operated Ca2+ channels
↓ Adenylyl cyclase↑ MAP kinases↑ GIRK channels
Extracellular
Cytoplasmic
Muscarinic acetylcholine receptor (mAChR)
Acetylcholine
M1, M3, M5 M2, M4
TM1
TM3
TM5
TM7
TM2
TM4
TM6
Gq/11 Gi/0
TM1
TM3
TM5
TM7
TM2
TM4
TM6
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Adrenergic receptors
Receptor
Gi
a2
Inhibition of transmitterrelease
Ca2+
Adenylyl cyclase
ATP cAMP
Smooth musclerelaxation
Gq
a1
Smooth muscle contraction
Ca2+
Phospholipase CPIP2
IP3
DAG
Gs
b
Heart muscle contractionSmooth muscle relaxation
Glycogenolysis
Adenylyl cyclase
ATP cAMP
Adrenalin, Noradrenalin
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Blocking the neuromuscular transmissiona-Bungarotoxin:• Snake venom (Bungarus multicinctus) • Binds to the N-Ach receptor and inactivatesCurare (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
