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

EXTRACELLULAR RECEPTORSION CHANNELS

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-2009-0011Scheme of the signal transduction of cell surface receptors

Ligand Receptor

Intracellularsignaling

Gene expression

Biological response

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Receptor families• Extracellular receptors: hidrophylic ligands eg.

peptide, protein hormones– Ion-channel receptors– 7-transmembrane-spanning receptors (7TM)– Catalytic receptors: intrinsic enzyme activity– Non-catalytic receptors: use cytoplasmic tyrosine

kinases• Intracellular receptors: lipophilic hormones eg.

steroids, thyroxin

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ENZYME-LINKED RECEPTORS

G-PROTEIN-LINKED RECEPTORS

ION-CHANNEL-LINKED RECEPTORS

Ions

Signalmolecule

Cytoplasm

Plasma membrane

GDP

gbaGTP

gba

gb

Enzyme Enzyme EnzymeGTP

a

Signal molecule

G-protein Activated G-protein Activated enzyme

Dimer of signal molecule

Inactivecatalyticdomain

Enzyme

Active catalyticdomain

Signal molecule

Activated enzyme

Extracellular receptor types

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Receptors

Ionotropic(ion-channel linked)

Metabotropic(use second messengers)

GABAA, GABAC, iGluGlycine,

Serotonin, Nicotinic Ach,

P2X

GABAB, mGlu, Adrenaline,

Noradrenaline, Glucagon, FSH, LH,

TSH, ADH, parathormone,growth-factors,

cytokines

Receptors

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GlucagonSecretin AdrenalineACTH LH FSH

Adenylyl cyclase

ATP cAMP

More receptors using the same second messenger system

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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, serotomine, 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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Functional groups of ligands

Inactive state Active state

Rr

Rr Rr

Inverse agonists AgonistsPartial agonists and

antagonists

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Ionotropic receptors (ligand-gated ion channels)

Ions

Ligand

Cytoplasm

Plasma membrane

Ligand gated ion channel

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Ion channel receptors• Cys-loop receptors: pentameric structure, 4

transmembrane (TM) regions/subunit – e.g., Acetylcholin (Ach) Nicotinic R – Na+ channel – e.g., GABAA, GABAC, Glycine – Cl- channels

(inhibitory role in CNS)• Glutamate-activated cationic channels: (excitatory

role in CNS), tetrameric stucture, 3 TM regions/subunit– e.g., iGlu

• ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit– e.g., P2X purinoreceptor

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Nicotinic Ach receptor

TOP

FRONT

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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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The axon terminal Axon of motor neuron

Terminal button

Axon terminal

Voltage-gatedNa+ channel

Acetylcholine

Muscle fiberNa+

Ca2+

Voltage-gated Ca2+ channel

Acetylcholinesterase

Vesicle of acethylcholine

K+

Neurotransmitter-gatedchannel

Motor end plate

1

2

3

4 5 6

7

~4x107 nicotinic Ach Rs / end plate

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Electric organs in animals

• Marine ray Torpedo• Freshwater electric eel Electrophorus • 2x1011 nicotinic Ach receptors/end

plate!

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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

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Acetylcholinesterase (AchE)• Quick removal of Ach from the synaptic space• Ach → choline+acetyl• Reversible inhibitors: therapeutic use (myasthenia,

glaucoma, Alzheimer’s)• Irreversble inhibitors: chemical weapons and

pesticides e.g. organophosphatesAch

AchE