Lluis, C. (Carmen)

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2009 - 20103

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    Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis
    (Sage Publications, 2010) Lluis, C. (Carmen); Conte-Perales, L. (L.); Lanciego, J.L. (José Luis); Rico, A.J. (Alberto J.); Roda, E. (Elvira); Lopez, I.P. (Iciar P.); Franco, R. (Rafael); Barroso-Chinea, P. (P.); Callen, L. (L.); Labandeira-Garcia, J.L. (José L.); Gomez-Bautista, V. (V.)
    The putative presence of the cannabinoid receptor type 2 (CB(2)-R) in the central nervous system is still a matter of debate. Although first described in peripheral and immune tissues, evidence suggesting the existence of CB(2)-Rs in glial cells and even neurons has been made available more recently. By taking advantage of newly designed CB(2)-R mRNA riboprobes, we have demonstrated by in situ hybridization and PCR the existence of CB2-R transcripts in a variety of brain areas of the primate Macaca fascicularis, including the cerebral cortex and the hippocampus, as well as in the external and internal divisions of the globus pallidus, both pallidal segments showing the highest abundance of CB(2)-R transcripts. In this regard, the presence of the messenger coding CB(2)-Rs within the pallidal complex highlights their consideration as potential targets for the treatment of movement disorders of basal ganglia origin.
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    Interactions between calmodulin, adenosine A2A, and dopamine D2 receptors
    (American Society for Biochemistry and Molecular Biology, 2009) Lluis, C. (Carmen); Canela, E.L. (E.L.); Lanciego, J.L. (José Luis); Cortes, A. (Antoni); Navarro, G. (Germán); Marcellino, D. (Daniel); Ferre, S. (Sergi); Aymerich-Soler, M.S. (María Soledad); Franco, R. (Rafael); Woods, A.S. (Amina S.); Casado, V. (Victoria); Mallol, J. (Josefa); Fuxe, K. (K.); Agnati, L. (Luigi)
    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.
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    Prime time for G-protein-coupled receptor heteromers as therapeutic targets for CNS disorders: the dopamine D₁-D₃ receptor heteromer
    (Bentham Science Publishers, 2010) Lluis, C. (Carmen); Lanciego, J.L. (José Luis); Ferre, S. (Sergi); Franco, R. (Rafael)
    A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that heteromer-tailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the heteromer. It can therefore be predicted that customized drugs targeting a specific receptor heteromer in the CNS might improve safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D₁-D₃ receptor heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinson's disease.