Manifestation of Novel Social Challenges of the European Un - PowerPoint Presentation

Slide1

Manifestation of Novel Social Challenges of the European Union

in the Teaching Material of

Medical Biotechnology Master’s

P

rogrammes

at the

University of

Pécs

and at the University of Debrecen

Identification

number

: TÁMOP-4.1.2-08/1/A-2009-0011Slide2

Signaling in the nervous system

Tímea Berki and Ferenc Boldizsár

Signal transduction

Manifestation of Novel Social Challenges of the European Union

in the Teaching Material of

Medical Biotechnology Master’s

P

rogrammes

at the

University of Pécs and at the University of Debrecen

Identification number

: TÁMOP-4.1.2-08/1/A-2009-0011Slide3

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-

neurotransmissionSlide4

Mechanism

of

neurotransmissionSynaptic

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 vesiclesSlide5

Receptors

Ionotropi

c

(

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, cytokinesReceptorsSlide6

Receptor -

ligand

interaction

Receptor

properties

LigandsLigand binds in the core region of

the 7 transmembrane helices11-cis-retinal (in rhodopsin)AcetylcholineCatecholaminesBiogenic amines (histamine,

serotonine, etc.)Nucleosides and nucleotidesLeukotrienes, prostaglandins, prostacyclins, ThromboxanesShort

peptide ligands bind partially in the core region and to the

external loopsPeptide hormones (ACTH, glucagon, growth hormone)Parathyroid

hormone, calcitoninLigands make several contacts with the N-terminal segment

and the external loopshypothalamic glycoprotein releasing factors (TRH, GnRH)Induce

an extensive reorganization of an extended N-terminal segmentMetabotropic 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 apparatusProteinase activated

receptorsReceptors for

thrombin amd thrypsinSlide7

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/subunitiGlu ATP-gated channels: 3 homologous subunits, 2 TM regions/subunitP2X purinoreceptorSlide8

7-transmembrane-spanning receptors

(7-TM)Class A:

Rhodopsin

-likeClass B: Secretin

familyClass C: Glutamate and GABA (metabotropic)FrizzledAdhesion familySlide9

7

-

TM ligands

Class A

Prostaglandins

ThromboxaneSerotonineDopamineHistamineCatecholaminesAch (M)

RhodopsinMelatoninChemokinesBradykininSomatostatinOpioidvasopressin

Class BGlucagonGnRHPTHCRH

Class CGlutamateGABASweet tastesSecretin

FrizzledWntHedgehogBitter tastes

AdhesionChondroitin-sulfateSlide10

Nicotinic Ach receptor

P

ore 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 CSlide11

Neurotransmission

Ions

GTP

a

Receptor

G-protein

is

activated

Effector

protein

Intracellular

messengers

G-protein subunits or intracellular

messengers modulate ion channels

Neurotransmitter

GTP

g

b

a

Cytoplasm

Plasma membrane

Neurotransmitter

Ion channel

Cytoplasm

Plasma

membraneSlide12

Acetylcholine





Ions pass through

the pore

Binding site for

neurotransmitter

Change in intracellular

ion contrentration

Five

assembled

subunits

(

2×



+

3×



)

of

nAChR

Extracellular

Cytoplasmic

COOH

NH

2

TM

1

TM

2

TM

3

TM

4

Extracellular

Cytoplasmic

Ligand

binding

site

Four

hydrophobic

transmembrane

domain

(TM1-4)

One subunit of nAChR

Nicotinic

acetylcholine

receptor (

nAChR

)

O

N

O

CH

3

H

3

C

H

3

C

CH

3

Acetylcholine

↑

PLC



↑ [Ca

2+

]

↑ MAP

kinases

↓ M current

↓ Voltage-operated

Ca

2+

channels

↓ Adenylyl cyclase

↑ MAP kinases

↑ GIRK channels

Extracellular

Cytoplasmic

Muscarinic

acetylcholine

receptor (

mAChR

)

Acetylcholine

M1, M3, M5

M2, M4

TM

1

TM

3

TM

5

TM

7

TM

2

TM

4

TM

6

Gq/11

Gi/0

TM

1

TM

3

TM

5

TM

7

TM

2

TM

4

TM

6Slide13

Adrenergic

receptors

Receptor

Gi



2

Inhibition

of

transmitter

release

Ca

2+

Adenylyl

cyclase

ATP

cAMP

Smooth muscle

relaxation

Gq



1

Smooth

muscle

contraction

Ca

2+

Phospholipase

C

PIP

2

IP

3

DAG

Gs



Heart

muscle

contraction

Smooth

muscle

relaxation

Glycogenolysis

Adenylyl

cyclase

ATP

cAMP

Adrenalin,

NoradrenalinSlide14

Blocking the neuromuscular transmission

a-

Bungarotoxin

:

S

nake 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 poisonCurare binds to the same place on the N-Ach receptor than Achetylcholin BUT channel doesn’t openCauses

paralysis of breathing musclesUsed as muscle relaxant in anaesthesiaAntidote: Acetylcholinesterase inhibitors