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Title: Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers
Author: Navarro Brugal, Gemma
Ferré, Sergi
Cordomí, Arnau
Moreno Guillén, Estefanía
Mallol Montero, Josefa
Casadó, Vicent
Cortés Tejedor, Antonio
Hoffmann, Hanne
Ortiz, Jordi
Canela Campos, Enric I.
Lluís i Biset, Carme
Pardo, Leonardo
Franco Fernández, Rafael
Woods, Amina S.
Keywords: Receptors cel·lulars
Interacció cel·lular
Cell receptors
Cell interaction
Issue Date: 27-Aug-2010
Publisher: American Society for Biochemistry and Molecular Biology
Abstract: G protein-coupled receptor (GPCR) heteromers are macromolecular complexes with unique functional properties different from those of its individual protomers. Little is known about what determines the quaternary structure of GPCR heteromers resulting in their unique functional properties. In the present study, using Resonance Energy Transfer (RET) techniques in experiments with mutated receptors, we provide for the first time clear evidence for a key role of intracellular domains in the determination of the quaternary structure of GPCR heteromers between adenosine A2A, cannabinoid CB1 and dopamine D2 receptors. In these interactions, arginine-rich epitopes form salt bridges with phosphorylated serine or threonine residues from CK1/2 consensus sites. Each receptor (A2A, CB1 and D2) was found to include two evolutionary conserved intracellular domains to establish selective electrostatic interactions with intracellular domains of the other two receptors, indicating that these particular electrostatic interactions constitute a general mechanism for receptor heteromerization. Mutation experiments indicated that the interactions of the intracellular domains of the CB1 receptor with A2A and D2 receptors are fundamental for the correct formation of the quaternary structure needed for the function (mitogen-activated protein kinase, MAPK, signaling) of the A2A-CB1-D2 receptor heteromers. Analysis of MAPK signaling in striatal slices of CB1 receptor KO mice and wild-type littermates supported the existence of A1-CB1-D2 receptor heteromer in the brain. These findings allowed us to propose the first molecular model of the quaternary structure of a receptor heteromultimer
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It is part of: Journal of Biological Chemistry, 2010, vol. 285, num. 35, p. 27346-27359
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ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Bioquímica i Fisiologia)

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