CODA-RET reveals functional selectivity as a result of GPCR heteromerization
| Autor: | Céline Galés, Rachel A. Kolster, Hideaki Yano, Nevin A. Lambert, Jonathan A. Javitch, Eneko Urizar |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Quinpirole Apomorphine medicine.drug_class Protein Conformation Dopamine Heteromer Protomer 7. Clean energy Article 03 medical and health sciences 0302 clinical medicine Dopamine receptor D1 GPCR Dopamine receptor D2 medicine Functional selectivity Fluorescence Resonance Energy Transfer Homomeric Humans Molecular Biology 030304 developmental biology G protein-coupled receptor 0303 health sciences dimerization Chemistry Receptors Dopamine D2 Receptors Dopamine D1 Cell Biology 3. Good health NPA Biochemistry Dopamine Agonists Biophysics functional selectivity Protein Multimerization 030217 neurology & neurosurgery |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 |
| Popis: | Here we present a new method that combines protein complementation with resonance energy transfer to study conformational changes in response to activation of a defined G protein-coupled receptor heteromer, and we apply the approach to the putative dopamine D1-D2 receptor heteromer. Remarkably, the potency of the D2 dopamine receptor (D2R) agonist R-(-)-10,11-dihydroxy-N-n-propylnoraporphine (NPA) to change the Gα(i) conformation via the D2R protomer in the D1-D2 heteromer was enhanced ten-fold relative to its potency in the D2R homomer. In contrast, the potencies of the D2R agonists dopamine and quinpirole were the same in the homomer and heteromer. Thus, we have uncovered a molecular mechanism for functional selectivity in which a drug acts differently at a G protein-coupled receptor (GPCR) protomer depending on the identity of the second protomer participating in the formation of the signaling unit--opening the door to enhancing pharmacological specificity by targeting differences between homomeric and heteromeric signaling. |
| Databáze: | OpenAIRE |
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