RT Journal Article
SR Electronic
T1 Functional Selectivity of Allosteric Interactions within GPCR oligomers: the Dopamine D1-D3 Receptor Heterotetramer
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.093096
DO 10.1124/mol.114.093096
A1 Xavier Guitart
A1 Gemma Navarro
A1 Estefania Moreno
A1 Hideaki Yano
A1 Ning-Sheng Cai
A1 Marta Sanchez
A1 Sandeep Kumar-Barodia
A1 Yamini Naidu
A1 Josefa Mallol
A1 Antoni Cortes
A1 Carme Lluis
A1 Enric I Canela
A1 Vicent Casado
A1 Peter J McCormick
A1 Sergi Ferre
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/08/05/mol.114.093096.abstract
AB The dopamine D1 receptor-D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa-induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques and cell signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R-D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and GI proteins, respectively. Co-activation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1 and to a positive crosstalk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive crosstalk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of YFP fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists.