TY - JOUR
T1 - CODA-RET reveals functional selectivity as a result of GPCR heteromerization
AU - Urizar, Eneko
AU - Yano, Hideaki
AU - Kolster, Rachel
AU - Galés, Céline
AU - Lambert, Nevin
AU - Javitch, Jonathan A.
N1 - Funding Information:
This work was supported in part by US National Institutes of Health (NIH) grants DA022413 and MH054137 (J.A.J.), GM078319 (N.L.) and NIH TL1 RR02415804 (H.Y.) as well as by the Lieber Center for Schizophrenia Research and Treatment and EMBO LongTerm and Basque Country fellowships (E.U.).
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.623
DO - 10.1038/nchembio.623
M3 - Article
C2 - 21785426
AN - SCOPUS:84860388929
SN - 1552-4450
VL - 7
SP - 624
EP - 630
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -