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

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

Research output: Contribution to journalArticle

82 Scopus citations

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 - Sep 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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