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

ION CHANNEL RECEPTORS

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

Ion channel receptors1 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) 2 Glutamate-activated cationic channels:

(excitatory role in CNS), tetrameric stucture, 3 TM regions/subunit– eg. iGlu

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

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Cys-loop ion-channel receptors

a bg

abp1p2

Receptor type

Subunit diversity a1-6, b1-3, g1-3, d,e,k, and q p1-3 a1-4, b

GABAA GABAC Glycine

TM1

TM2

TM3

TM4

N

CN

CN

C

NCNC

Pore

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Vertebrate anionic Cys-loop receptors

Type Class Protein name Gene Previous names

GABAA

alpha

a1a2a3a4a5a6

GABRA1GABRA2GABRA3GABRA4GABRA5GABRA6

EJM, ECA4

betab1b2b3

GABRB1GABRB2GABRB3

ECA5

gammag1g2g3

GABRG1GABRG2GABRG3

CAE2, ECA2, GEFSP3

delta d GABRD

epsilon e GABRE

pi p GABRP

theta q GABRQ

rho rGABRRGABRRGABRR

GABAC

Glycine (GlyR)alpha

a1a2a3a4

GLRA1GLRA2GLRA3GLRA4

STHE

beta b GLRB

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Vertebrate cationic Cys-loop receptors

Type Class Protein name Gene Previous names

Serotonin(5-HT)

5-HT3

5-HT3A5-HT3B5-HT3C5-HT3D5-HT3E

HTR3AHTR3BHTR3CHTR3DHTR3E

5-HT3A

5-HT3B

5-HT3C

5-HT3D

5-HT3E

Nicotinic acetylcholine(nAChR)

alpha

a1a2a3a4a5a6a7a8a9a10

CHRNA1CHRNA2CHRNA3CHRNA4CHRNA5CHRNA6CHRNA7CHRNA8CHRNA9

CHRNA10

ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS

beta

b1b2b3b4

CHRNB1CHRNB2CHRNB3CHRNB4

CMS2A, SCCMS, ACHRB, CHRNB, CMS1D, EFNL3, nAChRB2

gamma g CHRNG ACHRG

delta d CHRND ACHRD, CMS2A, FCCMS, SCCMS

epsilon e CHRNE ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS

Zinc-activated ion channel

ZAC ZACN ZAC1, L2m, LGICZ1

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Ionotropic glutamate receptors

Type Class Protein name Gene Previous names

AMPA GluA1

GluA1GluA2GluA3GluA4

GRIA1GRIA2GRIA3GRIA4

GLUA1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1GLUA2, GluR2, GluRB, GluR-B, GluR-K2, HBGR2

GLUA3, GluR3, GluRC, GluR-D, GluR-K3GLUA4, GluR4, GluRD, GluR-D

Kainate GluK

GluK1GluK2GluK3GluK4GluK5

GRIK1GRIK2GRIK3GRIK4GRI5

GLUK5, GluR5, GluR-5, EAA3GLUK6, GluR6, GluR-6, EAA4, GLUK7, GluR7, GluR-7, EAA5,

GLUK1, KA1, KA-1, EAA1GLUK2, KA2, KA-2, EAA2

NMDA

GluNGluN1NRL1ANRL1B

GRIN1GRINL1AGRINL1B

GLUN1, NMDA-R1, NR1, GluRz1

GluN2AGluN2BGluN2CGluN2D

GRIN2AGRIN2BGRIN2CGRIN2D

GLUN2A, NMDA-R2A, NR2A, GluRe1GLUN2B, NMDA-R2B, NR2B, GluRe2GLUN2C, NMDA-R2C, NR2C, GluRe3GLUN2D, NMDA-R2D, NR2D, GluRe4

GluN3AGluN3B

GRIN3AGRIN3B

GLUN3A, NMDA-R3A, NMDAR-L, chi-1GLUN3B, NMDA-R3B

‘Orphan’ (GluD)GluD1GluD2

GRID1GRID2

GluRd1

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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

Top Front

TÁMOP-4.1.2-08/1/A-2009-0011

Common neurotransmitters

Neurotransmitter Action Receptor subtypes

Acetylcholine (Ach) +/- Nicotinic, Muscarinic

Norepinephrine (NE) + 1/2, 1/2/3α β

Dopamine +/- D1-D4

Serotonin (5-HT) +/- 5-HT1A etc.

Glutamate (Glu) + NMDA, AMPA

GABA - GABAA, GABAB

Encephalins - , , μ κ δ

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Presynaptic neuron(axon terminal)

Postsynaptic neuron

Neurotransmitter molecule

NT transporter

Synaptic vesicles

Voltage-gated sodium channel

GPCR (modulatory

)

Ligand-gated ion channel

(direct excitation or inhibition)

+

+

Synapse between two neurons - neurotransmission

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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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NeurotransmittersAcetylcholine

Monoamines

Amino Acids

Purines

Neuropeptides

Soluble gases

Indolamines

Catecholamines

Opioids

Non-opioids

EndorphinsEnkephalinsDynorphins

NOCO

Acetylcholine (motor neurons)

Serotonin (memory, emotion)

m/i

m/i

Dopamine (motivation, addiction)Norepinephrine/Noradrenaline (sympathetic NS)Epinephrine

mmm

Glutamate (most prominent in CNS, excitatory)GABA (30%-40% of CNS synapses, inhibitory)AspartateGlycine (can be excit. or inhib. depending on Cl- conc.) *i

m/im/ii

AdenosineGuanosineATPOthers

i/mmm

Substance PNeuropeptide YOthers

m

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Acetylcholine receptors

Nicotinic Neuronal a2 (a-toxin insensitive)

Nicotinic Neuronal a3 (a-toxin insensitive)

Nicotinic Neuronal a4 (a-toxin insensitive)

Nicotinic Neuronal a5 (a-toxin insensitive)

Nicotinic Neuronal a5 (non-functional without a subunits)

Nicotinic Neuronal a6 (a-toxin insensitive)

Nicotinic Neuronal a7 (a-toxin sensitive)

Nicotinic Neuronal a8 (a-toxin sensitive)

Nicotinic Neuronal a9

Nicotinic Neuronal b2

Nicotinic Neuronal b3

Nicotinic Neuronal b4

Nicotinic Neuronal b5

Nicotinic musclePhenyltrimethyl-ammoniumElapid a-toxins, d-Tubocurarine

Nicotinic Junctional [(a1)2bed]

Nicotinic Embyonic [(a1)2bgd]

Nicotinic neuronal (a+b)Dimethylphenyl-piperazinuim,CystineTrimethaphanNeuronal bungarotoxin

OxotremorinePropyllbenzilylcholine mustardQuinuclidinyl benzilate

Muscarinic m5-M5

Muscarinic m1-M1Pirenzepine

Muscarinic m2-M2Methoctramine

Muscarinic m3-M3Hexahydro-siladifenidol

Muscarinic m4-M4Himbacine

NicotinicNicotined-Tubocurarine

MuscarinicMuscarine, PilocarpineAtropine

CholinergicAcetylcholine

Stage 1 Stage 2 Stage 3

TÁMOP-4.1.2-08/1/A-2009-0011

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

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

pesticides eg. organophosphatesAch

AchE