RT Journal Article
T1 Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.
A1 Ruso-Julve, Fulgencio
A1 Pombero, Ana
A1 Pilar-Cuéllar, Fuencisla
A1 García-Díaz, Nuria
A1 Garcia-Lopez, Raquel
A1 Juncal-Ruiz, María
A1 Castro, Elena
A1 Díaz, Álvaro
A1 Vazquez-Bourgón, Javier
A1 García-Blanco, Agustín
A1 Garro-Martinez, Emilio
A1 Pisonero, Helena
A1 Estirado, Alicia
A1 Ayesa-Arriola, Rosa
A1 López-Giménez, Juan
A1 Mayor, Federico
A1 Valdizán, Elsa
A1 Meana, Javier
A1 Gonzalez-Maeso, Javier
A1 Martínez, Salvador
A1 Vaqué, José Pedro
A1 Crespo-Facorro, Benedicto
AB A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.
YR 2019
FD 2019-11-18
LK http://hdl.handle.net/10668/14709
UL http://hdl.handle.net/10668/14709
LA en
DS RISalud
RD Apr 4, 2025