competitive v.s. non-competitive antagonists
DESCRIPTION
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 PresentationTRANSCRIPT
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
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
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
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)