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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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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)

ION CHANNEL RECEPTORS

Tímea Berki and Ferenc Boldizsár Signal transduction

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

(3)

Ion channel receptors

1 Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit

– Acetylcholin (Ach) Nicotinic R – Na + channel

– GABA A , GABA C, 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

(4)

Cys-loop ion-channel receptors

a b g

a b p1

p2 Receptor type

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

GABAA GABAC Glycine

TM 1

TM 2

TM 3

TM 4 N

C

N

C N

C C N N C

Pore

(5)

Vertebrate anionic Cys-loop receptors

Type Class Protein name Gene Previous names

GABAA

alpha

a1 a2 a3 a4 a5 a6

GABRA1 GABRA2 GABRA3 GABRA4 GABRA5 GABRA6

EJM, ECA4

beta

b1 b2 b3

GABRB1 GABRB2

GABRB3 ECA5

gamma

g1 g2 g3

GABRG1 GABRG2

GABRG3 CAE2, ECA2, GEFSP3

delta d GABRD

epsilon e GABRE

pi p GABRP

theta q GABRQ

rho r GABRR

GABRR

GABRR GABAC

Glycine (GlyR) alpha

a1 a2 a3 a4

GLRA1 GLRA2 GLRA3 GLRA4

STHE

beta b GLRB

(6)

Vertebrate cationic Cys-loop receptors

Type Class Protein name Gene Previous names

Serotonin

(5-HT) 5-HT3

5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E

HTR3A HTR3B HTR3C HTR3D HTR3E

5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E

Nicotinic acetylcholine (nAChR)

alpha

a1 a2 a3 a4 a5 a6 a7 a8 a9 a10

CHRNA1 CHRNA2 CHRNA3 CHRNA4 CHRNA5 CHRNA6 CHRNA7 CHRNA8 CHRNA9 CHRNA10

ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS

beta

b1 b2 b3 b4

CHRNB1 CHRNB2 CHRNB3 CHRNB4

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

(7)

Ionotropic glutamate receptors

Type Class Protein name Gene Previous names

AMPA GluA1

GluA1 GluA2 GluA3 GluA4

GRIA1 GRIA2 GRIA3 GRIA4

GLUA1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1 GLUA2, GluR2, GluRB, GluR-B, GluR-K2, HBGR2

GLUA3, GluR3, GluRC, GluR-D, GluR-K3 GLUA4, GluR4, GluRD, GluR-D

Kainate GluK

GluK1 GluK2 GluK3 GluK4 GluK5

GRIK1 GRIK2 GRIK3 GRIK4 GRI5

GLUK5, GluR5, GluR-5, EAA3 GLUK6, GluR6, GluR-6, EAA4, GLUK7, GluR7, GluR-7, EAA5,

GLUK1, KA1, KA-1, EAA1 GLUK2, KA2, KA-2, EAA2

NMDA

GluN

GluN1 NRL1A NRL1B

GRIN1 GRINL1A

GRINL1B GLUN1, NMDA-R1, NR1, GluRz1 GluN2A

GluN2B GluN2C GluN2D

GRIN2A GRIN2B GRIN2C GRIN2D

GLUN2A, NMDA-R2A, NR2A, GluRe1 GLUN2B, NMDA-R2B, NR2B, GluRe2 GLUN2C, NMDA-R2C, NR2C, GluRe3 GLUN2D, NMDA-R2D, NR2D, GluRe4 GluN3A

GluN3B GRIN3A

GRIN3B GLUN3A, NMDA-R3A, NMDAR-L, chi-1 GLUN3B, NMDA-R3B

‘Orphan’ (GluD) GluD1

GluD2 GRID1

GRID2 GluRd1

(8)

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

(9)

Common neurotransmitters

Neurotransmitter Action Receptor subtypes

Acetylcholine (Ach) +/- Nicotinic, Muscarinic

Norepinephrine (NE) + α1/2, β1/2/3

Dopamine +/- D1-D4

Serotonin (5-HT) +/- 5-HT1 A etc.

Glutamate (Glu) + NMDA, AMPA

GABA - GABA A , GABA B

Encephalins - μ, κ, δ

(10)

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

(11)

Neurotransmission

Ions

GTP a

Receptor

G-protein is activated

Effector protein

Intracellular messengers

G-protein subunits or intracellular messengers modulate ion channels Neurotransmitter

GTP b g Cytoplasm a

Plasma membrane

Neurotransmitter

Ion channel

Cytoplasm

Plasma membrane

(12)

Neurotransmitters

Acetylcholine

Monoamines

Amino Acids

Purines

Neuropeptides

Soluble gases

Indolamines

Catecholamines

Opioids

Non-opioids

Endorphins Enkephalins Dynorphins

NO CO

Acetylcholine (motor neurons) Serotonin (memory, emotion)

m/i

m/i Dopamine (motivation, addiction)

Norepinephrine/Noradrenaline (sympathetic NS) Epinephrine

m m m Glutamate (most prominent in CNS, excitatory)

GABA (30%-40% of CNS synapses, inhibitory) Aspartate

Glycine (can be excit. or inhib. depending on Cl- conc.) * i m/i m/i i

Adenosine Guanosine ATP Others

i/m m m

Substance P Neuropeptide Y Others

m

(13)

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 muscle

Phenyltrimethyl-ammonium Elapid a-toxins, d-Tubocurarine

Nicotinic Junctional [(a1)2bed]

Nicotinic Embyonic [(a1)2bgd]

Nicotinic neuronal (a+b) Dimethylphenyl-piperazinuim, Cystine

Trimethaphan Neuronal bungarotoxin

Oxotremorine

Propyllbenzilylcholine mustard Quinuclidinyl benzilate

Muscarinic m5-M5

Muscarinic m1-M1 Pirenzepine Muscarinic m2-M2 Methoctramine

Muscarinic m3-M3 Hexahydro-siladifenidol Muscarinic m4-M4 Himbacine

Nicotinic Nicotine d-Tubocurarine

Muscarinic

Muscarine, Pilocarpine Atropine

Cholinergic Acetylcholine

Stage 1 Stage 2 Stage 3

(14)

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.

organophosphates

Ach

AchE

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