Competitive v.s. non-competitive antagonists.

Competitive v.s. non-competitive antagonists. and / or RECEPTOR RECEPTOR RECEPTOR RECEPTOR DIFFERENT BINDING SITES BINDING SITES OVERLAP

Inverse agonism

K1 R AR A K1 R AR L M K2 L M R* AR* RG ARG K3 aK3 K2 R*G AR*G 1980: "Ternary complex model" by De Lean et al. bK2 receptors have access to all G proteins at cell surface H.R.G complex is usually high agonist affinity state Models for GPCR activation and G protein coupling B 1993: “Extended ternary complex model” by Samama et al.

Effect of receptor reserve on agonist potency

Desensitization Internalization Down-regulation Mechanisms that regulate signaling ofG protein-coupled receptors

G protein-coupled receptors (GPCRs) are desensitised through the concerted actions of GPCR kinases (GRKs) and ß-arrestins Perry and FergusonTrends in Cell Biol. (2002)

Biological functions of ß-arrestin bg bg Ga Ga P P P P 3. Activation of MAP kinase signaling AP2 A 1. Receptor desensitization ß-arrestin Clathrin 2. Receptor internalization

ligand ligand Rluc Rluc eYFP energy transfer Blue light 480 nm emitted light Rluc Bioluminescence Resonance Energy Transfer (BRET)

Angiotensin II-induced interaction between barrestin2-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 signalingcomplexes

Molecular mechanisms involved in the GRK- and ß-arrestin-dependent desensitisation and internalisation of GPCRs Ferguson, S.S.G.; Pharmacol. Rev. (2001)

Regulation of G-protein coupled receptor function

Competitive v.s. non-competitive antagonists.