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Competitive v.s. non-competitive antagonists. receptor competitive antagonist receptor non-competitive, allosteric antagon agonist response receptor non-competitive, functional antagonist agonist response receptor BINDING SITES OVERLAP DIFFERENT BINDING SITES RECEPTOR RECEPTOR RECEPTOR RECEPTOR and / or

Competitive v.s. non-competitive antagonists

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Competitive v.s. non-competitive antagonists. and / or. RECEPTOR. RECEPTOR. RECEPTOR. RECEPTOR. DIFFERENT BINDING SITES. BINDING SITES OVERLAP. Inverse agonism. K 1. R. AR. A. K 1. R. AR. L. M. K 2. L. M. R*. AR*. RG. ARG. K 3. a K 3. K 2. R*G. AR*G. - PowerPoint PPT Presentation

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Competitive v.s. non-competitive antagonists.

receptor

competitive antagonist

receptor

non-competitive, allosteric antagonist

agonist

response

receptor

non-competitive, functional antagonist

agonist

response

receptor

BINDING SITESOVERLAP

DIFFERENT BINDING SITES

RECEPTOR RECEPTORRECEPTOR RECEPTOR

and / or

Inverse agonism

R ARK1

L M

R* AR*

R*G AR*GK2

K2

K3 K3

B

Models for GPCR activation and G protein coupling

1993: “Extended ternary complex model” by Samama et al.

R AR

RG ARGK2

K1

L M

A

1980: "Ternary complex model" by De Lean et al.

receptors have access to all G proteins at cell surface

H.R.G complex is usually high agonist affinity state

Effect of receptor reserve on agonist potency

Mechanisms that regulate signaling of

G protein-coupled receptorsDesensitization Internalization

Down-regulation

G protein-coupled receptors (GPCRs)G protein-coupled receptors (GPCRs) are are desensitidesensitissed through the concerted actions of ed through the concerted actions of

GGPCRPCR kinases (GRKs) and kinases (GRKs) and ßß-arrestins-arrestins

Perry and Ferguson Trends in Cell Biol. (2002)

Biological functions of ß-arrestin

ß-arrestin

1. Receptor desensitization

3. Activation of MAP kinase signaling

2. Receptor internalization

GG

A

emitted light

ligand ligand

eYFP

Blue light 480 nm

energy transfer

RlucRlucRluc

BioluminescenceResonanceEnergy Transfer(BRET)

[Ang II] (nmol/l)

0,1 1 10 100 1000

BR

ET

rat

io

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0,14

Angiotensin II-induced interaction between

arrestin2-renilla luciferase and AT1A receptor-YFP

Angiotensin II causes dose-dependent direct association of the AT1 receptor

with ß-arrestin2

Biological functions of ß-arrestins:

- Receptor desensitization

- Receptor endocytosis

- Organization of signaling complexes

Molecular mechanisms involved in the GRK- and ß-Molecular mechanisms involved in the GRK- and ß-arrestin-dependent desenarrestin-dependent desenssitiitissation and internaliation and internalissation ation

of GPCRsof GPCRs

Ferguson, S.S.G.; Pharmacol. Rev. (2001)

Regulation of G-protein coupled receptor function