Heteromerización de receptores de adenosina A2A, dopamina D2 y cannabinoides CB1. Implicaciones farmacológicas y funcionales.
ENGLISH SUMMARY: Classically G coupled receptors (GPCR) have been considered as individual units. However nowadays is accepted that these proteins could interact with others GPCRs, generating new properties to the receptors. In the central nervous system, the receptor-receptor interactions could be involved in the neurotransmission and neuromodulation. Thus, the malfunction of these systems could cause neurodegenerative diseases. In this context, the goals of this Thesis are focussed to study 1) the relevance of heteromerization in the functional properties of GPCR and their regulation and 2) the importance of describing heteromeric complexes of more than two receptors for the better understanding of biological functions. There are evidences of functional and molecular interactions between A2AR and D2R that are relevant in Parkinson disease. These patients are treated with L-DOPA, which is metabolized to dopamine. However, some L-DOPA is metabolized to homocysteine. The paper Allosteric Modulation of Dopamine D2 Receptors by Homocysteine (Journal of Proteome Research (2006)), shows the effect of this compound in the functionality and regulation of A2AR/D2R heteromer. Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids (Neuropsychopharmacology (2007)), opens a new perspective to unravelling the regulation of these two receptors in the striatum. The A2AR and CB1R participate in motor control and drug addition, but their functional interactions evidences are only indirect. This paper, not only describes the molecular interaction between A2AR and CB1R, but also the role of heteromerization in motor control. One of the most remarkable goals of this Thesis is the develop of the SRET technique, described in Detection of Heteromerization of More than Two Receptors by Sequential BRET-FRET (unpublished results). This technique is very useful for the descriptions of complexes of more than two receptors: 1) important to understand the integrated signals at molecular level, and 2) to design new compounds for the treatment of diseases. Also, we described for the first time the occurrence of complexes between A2AR, D2R and CB1R and their implications in striatal function. Finally, in the article Insight into the intramembrane and intracellular cross-talk between adenosine A2A, dopamine D2 and cannabinoid CB1 receptor in the heteromer complex (unpublished results) we analyze the consequences of one of the receptorss activation in the heterotrimer. These results will help us to clear up the relationships among these three receptors in the striatopallidal GABAergic neurons.