Principal Investigators

Sergi Ferré, M.D., Ph.D., Senior Investigator

Chief, Integrative Neurobiology Section

Post-doctoral Training - Karolinska Institute, Stockholm

Neurologist - Residency training in the Department of Neurology, Hospital de Sant Pau, Faculty of Medicine, Universitat Autònoma de Barcelona

Ph.D. - Laboratory of Neuropharmacology, Faculty of Medicine, Universitat Autònoma de Barcelona

M.D. - Faculty of Medicine, Universitat Central de Barcelona

RESEARCH INTERESTS

We are interested in the role of receptor heteromers as targets for drug development in neuropsychiatric disorders and drug addiction. Receptor heteromers are higher order molecular entities that are the result of combinatorial evolution and endowed with unique biochemical and functional properties that could be harnessed for therapeutic purposes. Receptor heteromers uncover a previously unforeseen vast number of new possible subpopulations of G-protein-coupled receptor subtypes, with specific neuronal localizations and functions. Their potential ligand selectivity implies that receptor heteromers constitute potential new targets for drug development.

Our research deals preferentially with the discovery of heteromers of receptors that are targets for addictive drugs or that are localized in brain circuits that are involved in addictive behaviors (such as dopamine, glutamate, cannabinoid and adenosine receptors) and with the analysis of their biochemical and pharmacological properties involving studies at the cellular level as well as at the in vivo level.

At the cellular level, mammalian cell lines transfected with the receptors under study are used to demonstrate receptor heteromerization by protein-protein interaction experiments. We then look for the unique biochemical properties of the receptor heteromer, which can be used as a “biochemical fingerprint” for its identification in the brain. In vivo models are established for the evaluation of the functional significance of receptor heteromers, which include intracranial electrical stimulation, in vivo microdialysis and functional magnetic resonance imaging. The cellular and in vivo models complement each other and are then used to find receptor heteromer-selective drugs.

Selected Publications:

1. Ferré S, von Euler G, Johansson B, Fredholm BB, Fuxe K (1991) Stimulation of high affinity adenosine A-2 receptors decreases the affinity of dopamine D-2 receptors in rat striatal membranes. Proc Natl Acad Sci USA 88:7238-7241.

2. Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20:482-487.
   

3. Ginés S, Hillion J, Torvinen M, Le Crom S, Casadó V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Vernier P, Lluis C, Ferré S, Fuxe K, Franco R (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA 97:8606-8611.

4. Ferré S, Karcz-Kubicha M, Hope BT, Popoli P, Burgueno J, Casado V, Fuxe K, Lluis C, Goldberg SR, Franco R, Ciruela F (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: Implications for striatal neuronal function. Proc Natl Acad Sci USA 99:11940-11945.

5. Agnati LF, Ferré S, Lluis C, Franco R, Fuxe K (2003) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol Rev 55:509-550.

6. Carriba P, Navarro G, Ciruela F, Ferré S, Casado V, Agnati LF, Cortes A, Mallol J, Fuxe K, Canela EI, Lluis C, Franco R (2008) Detection of heteromerization of more than two proteins by sequential BRET-FRET. Nat Methods 5:727-733.

7. Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KDG, Pin J-P, Volkow N, Waldhoer M, Woods AS, Franco R (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131-134.

8. Navarro G, Moreno E, Aymerich M, Marcellino D, McCormick PJ, Mallol J, Cortés A, Canela EI, Ortiz J, Fuxe JK, Lluís C, Ferré S, Franco R (2010) Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine. Proc Natl Acad Sci USA 107:18676-18681.

9. Gonzalez S, Rangel-Barajas C, Peper M, Lorenzo R, Moreno E, Ciruela F, Borycz J, Ortiz J, Lluis C, Franco R, McCormick PJ, Volkow ND, Rubinstein M, Floran B, Ferré S (2012) Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain. Mol Psychiat 17:650-662.

10. Gonzalez S, Moreno-Delgado D, Moreno E, Perez-Capote K, Franco R, Mallol J, Casado V, Lluis C, Ortiz J, Ferré S, Canela E, McCormick PJ (2012) Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol 10:e1001347.