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Instituto de Parasitología y Biomedicina
"López - Neyra"
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[ Staff | Summary of Research | Funding Agencies | Publications | Doctoral Theses | Patents | Teaching]




SEROTONERGIC PSYCHEDELICS AND NEURONAL PLASTICITY



Group Leader
    • Juan Francisco López Giménez     
        email: jf.lopez.gimenez (@ipb.csic.es)
        Tlf: 958181657



    Staff Research Predoctoral
    • Marco Taddei Tardón     


    Authorized Staff
    • Hortensia Guadalupe Luna Cuevas     
    • Egoa Ugarte Pérez     
    • Shahinaz Yasser Mossad     

     

    SUMMARY OF RESEARCH


     

    SUMMARY OF RESEARCH

     

    Our research group is devoted in the study of the molecular pharmacology of G-protein coupled receptors (GPCRs) considering structural and functional aspects of these membrane proteins at the cellular level. We are focusing our present investigations in 5-HT2A serotonin receptors, more particularly these ones expressed in the central nervous system (CNS). The canonical mode of action of GPCRs consists in their coupling to heterotrimeric G proteins upon binding to selective compounds known as agonists leading to the activation/modulation of intracellular effectors such as adenylyl cyclases, different phospholipases and others. Nevertheless, it has been recently described other possible mechanisms to initiate cellular signaling processes after receptor activation such as the interaction with Β-arrestins.


    The possibility that a single GPCR may activate different signaling pathways brought the concept of functional selectivity or biased agonism defined as the capability of some ligands to initiate different signaling pathways interacting with the same receptor. In this respect, 5-HT2A receptor constitutes a paradigm of functional selectivity due to the different signaling profiles evoked depending on the chemical nature of the activating agonist. In this sense, 5-HT2A receptor agonists can be grouped according to those different signaling responses and, interestingly, these two groups correspond with ligands presenting hallucinogenic and non-hallucinogenic properties.


     
     


    These 5-HT2A receptor agonists showing hallucinogenic properties when administered in human subjects are also known as psychedelics. Recently, interest in psychedelics have arisen as a potential therapeutic tool for treating mental disorders such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD) and addiction among others. One of the most accepted hypothesis at the moment considers that psychedelic therapeutic potential is based in their capacity of modulating neuronal circuitry by inducing plastinogenic processes at the neuronal level. In this sense, understanding the molecular mechanisms mediating psychedelic therapeutic effects is mandatory in order to optimize their use in the clinical practice as well as to discover and develop new compounds showing similar pharmacological properties.


    One of our main research interest currently is going in depth into the molecular and pharmacological mechanisms involved in the action of serotonergic psychedelics on neuronal plasticity by exploring alternative molecular targets using an innovative in vitro experimental model.

    We have stablished in our laboratory an in vitro cellular model derived from neural progenitors isolated from mouse fetuses. These neural progenitors are proliferative and susceptible to be differentiated into the distinctive neural lineages, i.e., neurons and glial cells. We have characterized neurons obtained in such way as glutamatergic in terms of their neurochemical phenotype and expressing 5-HT2A receptors.


     
     


    Moreover, we have set up an assay to evaluate neuronal synaptogenesis in cultured neurons based on the rabies virus technology. This methodological approach constitutes currently an unique monosynaptic tracer to unambiguously label direct connected neurons.

     
     



     


    FUNDING AGENCIES LAST 5 YEARS

    - GENERACION DE UN NUEVO MODELO CELULAR DE ESQUIZOFRENIA PARA EL AVANCE EN EL CONOCIMIENTO DEL MECANISMO DE ACCION DE LOS ANTIPSICOTICOS. PROYECTO, PN2018 - Proyectos I+D+i «Retos Investigación», Ref: RTI2018-097344-B-I00, (2019 - 2022).

     

     

    PUBLICATIONS LAST 5 YEARS

    -Martín-Guerrero, S.M.; Alonso, P.; Iglesias, A.; Cimadevila, M.; Brea, J.; Loza, M.I.; Casado, P.; Martín-Oliva, D.; Cutillas, P.R.; González-Maeso, J.; López-Giménez, J.F., His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics, Biochemical Pharmacology, 2021, Vol. 185: 114440, ARTÍCULO, Id:844111

    -Toneatti, R.; Shin, J.M.; Shah, U.H.; Mayer, C.R.; Saunders, J.M.; Fribourg, M.; Arsenovic, P.T.; Janssen, W.G.; Sealfon, S.C.; López-Giménez, J.F.; Benson, D.L.; Conway, D.E.; González-Maeso, J., Interclass GPCR heteromerization affects localization and trafficking, Science signaling, 2020, Vol. 13: 654-eaaw3122, ARTÍCULO, Id:817263

    -Cimadevila, M.; Gómez-García, L.; Martínez, A.L.; Iglesias, A.; López-Giménez, J.; Castro, M.; Cadavid, M.I.; Loza, M.I.; Brea, J., Essential role of the C148–C227 disulphide bridge in the human 5-HT2A homodimeric receptor, Biochemical Pharmacology, 2020, Vol. 177: 113985, ARTÍCULO, Id:806545

    -Ruso-Julve, F.; Pombero, A.; Pilar-Cuéllar, F.; García-Díaz, N.; Garcia-Lopez, R.; Juncal-Ruiz, M.; Castro, E.; Díaz, Á.; Vazquez-Bourgón, J.; García-Blanco, A.; Garro-Martinez, E.; Pisonero, H.; Estirado, A.; Ayesa-Arriola, R.; López-Giménez, J.; Mayor, F.; Valdizán, E.; Meana, J.; Gonzalez-Maeso, J.; Martínez, S.; Vaqué, J.P.; Crespo-Facorro, B., Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics, Translational psychiatry, 2019, Vol. 9: 1-306, ARTÍCULO, Id:780953

    -Martín-Guerrero, S.M.; Casado, P.; Muñoz-Gámez, J.A.; Carrasco, M.C.; Navascués, J.; Cuadros, M.A.; López-Giménez, J.F.; Cutillas, P.R.; Martín-Oliva, D., Poly(ADP-Ribose) Polymerase-1 inhibition potentiates cell death and phosphorylation of DNA damage response proteins in oxidative stressed retinal cells, Experimental Eye Research, 2019, Vol. 188: 107790, ARTÍCULO, Id:771412

    -Gómez, A.I.; Cruz, M.; López-Giménez, J.F., Evaluating the pharmacological response in fluorescence microscopy images: The Δm algorithm, PLoS ONE, 2019, Vol. 14: 2-e0211330, ARTÍCULO, Id:761605


     

     

    DOCTORAL THESES LAST 5 YEARS

     

    2018

    Rocío Pérez Gómez

    Analysis of the function of Sp6 and Sp8 transcription factors in the limb ectoderms.

    Instituto de Biomedicina y Biotecnología de Cantabria. (IBBTEC-CSIC). Universidad de Cantabria

     

     

     

     


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