PMID:19632986

Citation	Navarro, G, Aymerich, MS, Marcellino, D, Cortés, A, Casadó, V, Mallol, J, Canela, EI, Agnati, L, Woods, AS, Fuxe, K, Lluís, C, Lanciego, JL, Ferré, S and Franco, R (2009) Interactions between calmodulin, adenosine A2A, and dopamine D2 receptors. J. Biol. Chem. 284:28058-68
Abstract	The Ca(2+)-binding protein calmodulin (CaM) has been shown to bind directly to cytoplasmic domains of some G protein-coupled receptors, including the dopamine D(2) receptor. CaM binds to the N-terminal portion of the long third intracellular loop of the D(2) receptor, within an Arg-rich epitope that is also involved in the binding to G(i/o) proteins and to the adenosine A(2A) receptor, with the formation of A(2A)-D(2) receptor heteromers. In the present work, by using proteomics and bioluminescence resonance energy transfer (BRET) techniques, we provide evidence for the binding of CaM to the A(2A) receptor. By using BRET and sequential resonance energy transfer techniques, evidence was obtained for CaM-A(2A)-D(2) receptor oligomerization. BRET competition experiments indicated that, in the A(2A)-D(2) receptor heteromer, CaM binds preferentially to a proximal C terminus epitope of the A(2A) receptor. Furthermore, Ca(2+) was found to induce conformational changes in the CaM-A(2A)-D(2) receptor oligomer and to selectively modulate A(2A) and D(2) receptor-mediated MAPK signaling in the A(2A)-D(2) receptor heteromer. These results may have implications for basal ganglia disorders, since A(2A)-D(2) receptor heteromers are being considered as a target for anti-parkinsonian agents.
Links	PubMed PMC2788857 Online version:10.1074/jbc.M109.034231
Keywords	Adenosine/metabolism; Amino Acid Sequence; Animals; Calmodulin/chemistry; Calmodulin/genetics; Calmodulin/metabolism; Cell Line; Dopamine/metabolism; Fluorescence Resonance Energy Transfer/methods; Humans; MAP Kinase Signaling System/physiology; Male; Molecular Sequence Data; Multiprotein Complexes; Protein Multimerization; Protein Structure, Tertiary; Proteomics/methods; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A/chemistry; Receptor, Adenosine A2A/genetics; Receptor, Adenosine A2A/metabolism; Receptors, Dopamine D2/chemistry; Receptors, Dopamine D2/genetics; Receptors, Dopamine D2/metabolism; Recombinant Fusion Proteins/chemistry; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism
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