CODA-RET reveals functional selectivity as a result of GPCR heteromerization

Eneko Urizar, Hideaki Yano, Rachel Kolster, Céline Galés, Nevin A Lambert, Jonathan A. Javitch

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)624-630
Number of pages7
JournalNature Chemical Biology
Volume7
Issue number9
DOIs
StatePublished - Jan 1 2011

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Dopamine D2 Receptors
Protein Subunits
G-Protein-Coupled Receptors
Dopamine Agonists
Quinpirole
Dopamine D1 Receptors
Energy Transfer
Dopamine
Pharmacology
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

CODA-RET reveals functional selectivity as a result of GPCR heteromerization. / Urizar, Eneko; Yano, Hideaki; Kolster, Rachel; Galés, Céline; Lambert, Nevin A; Javitch, Jonathan A.

In: Nature Chemical Biology, Vol. 7, No. 9, 01.01.2011, p. 624-630.

Research output: Contribution to journalArticle

Urizar, Eneko ; Yano, Hideaki ; Kolster, Rachel ; Galés, Céline ; Lambert, Nevin A ; Javitch, Jonathan A. / CODA-RET reveals functional selectivity as a result of GPCR heteromerization. In: Nature Chemical Biology. 2011 ; Vol. 7, No. 9. pp. 624-630.
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