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(1)

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)

EXTRACELLULAR RECEPTORS

ION CHANNELS

Tímea Berki and Ferenc Boldizsár Signal transduction

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

Scheme of the signal transduction of cell surface receptors

Ligand Receptor

Intracellular signaling

Gene expression

Biological response

(4)

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

(5)

ENZYME-LINKED RECEPTORS G-PROTEIN-LINKED RECEPTORS ION-CHANNEL-LINKED RECEPTORS

Ions

Signal molecule

Cytoplasm Plasma membrane

GDP b g a

GTP b g a

b g

Enzyme Enzyme Enzyme

GTP a Signal molecule

G-protein Activated G-protein Activated enzyme

Dimer of signal molecule

Inactive catalytic domain

Enzyme Active catalytic

domain

Signal molecule

Activated enzyme

Extracellular receptor types

(6)

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

(7)

Glucagon Secretin Adrenaline

ACTH LH FSH

Adenylyl cyclase

ATP cAMP

More receptors using the same

second messenger system

(8)

Receptor - ligand interaction

Receptor properties Ligands

Ligand binds in the core region of the 7 transmembrane helices

11-cis-retinal (in rhodopsin) Acetylcholine

Catecholamines

Biogenic amines (histamine, serotomine, 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)

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

(9)

Functional groups of ligands

Inactive state Active state

R r

R

r r R

Inverse agonists Agonists

Partial agonists and antagonists

(10)

channels)

Ions

Ligand

Cytoplasm

Plasma membrane

Ligand gated ion channel

(11)

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

(12)

Nicotinic Ach receptor

TOP

FRONT

(13)

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

(14)

The axon terminal

Axon of motor neuron

Terminal button

Axon terminal

Voltage-gated Na+ channel

Acetylcholine

Muscle fiber Na+

Ca2+

Voltage-gated Ca2+ channel

Acetylcholinesterase

Vesicle of acethylcholine

K+ Neurotransmitter-gated

channel

Motor end plate

1

2

3

4 5 6

7

~4x107 nicotinic Ach Rs / end plate

(15)

Electric organs in animals

• Marine ray Torpedo

• Freshwater electric eel Electrophorus

• 2x10

11

nicotinic Ach receptors/end plate!

(16)

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

(17)

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.

organophosphates

Ach

AchE

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