Sergi Ferré, M.D., Ph.D. is working as the 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

We are interested in the role of G protein-coupled receptor (GPCR) oligomers as targets for drug development in neuropsychiatric disorders. GPCR oligomers 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. Our studies are leading to a new theoretical view of GPCR physiology and pharmacology. The pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein seems to provide a main functional unit and oligomeric entities can be viewed as multiples of dimers. GPCR heteromers can then be preferentially constituted by heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer provides the frame for canonical antagonistic interactions between Gs- and Gi- coupled receptors. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. We have demonstrated that some general mechanisms apply particularly at the level of ligand-binding properties. But in addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Our research deals preferentially with the discovery of GPCR heteromers that are already targets for addictive drugs or that are localized in brain circuits that are involved in Substance Use Disorders (such as opioid, dopamine, glutamate and cannabinoid 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. Their properties imply multiple allosteric mechanisms as well as their ability to form part of specific GPCR-G protein-effector macromolecular complexes. Finally, we are also studying the role of GPCR heteromers in determining functional differences of the products of polymorphic variants associated with endophenotypes of neuropsychiatric disorders. At the cellular level, mammalian cell lines transfected with the receptors under study are used to demonstrate GPCR heteromerization by biophysical techniques. We then investigate the unique biochemical properties of the GPCR heteromers using biochemical disruptive techniques, which provide a “biochemical fingerprint” for their identification in the brain. In vivo models are established for the evaluation of the functional significance of GPCR heteromers, which include combinations of intracranial electrical and optogenetic stimulation and in vivo microdialysis techniques.