FXR1P is a GSK3β substrate regulating mood and emotion processing
| Autor: | Tiziana Quarto, Camille Latapy, Jivan Khlghatyan, Barbara Gelao, Thomas Del’Guidice, Claude Lamarre, Morgane Lemasson, Alessandro Bertolino, Annie Barbeau, Jean-Martin Beaulieu, Giuseppe Blasi, Giuseppe Rizzo, Antonio Rampino |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Genotype medicine.drug_class Movement Emotions Prefrontal Cortex Motor Activity Polymorphism Single Nucleotide Glycogen Synthase Kinase 3 Mice Young Adult GSK-3 medicine Animals Humans Bipolar disorder Phosphorylation GSK3B Mice Knockout Regulation of gene expression Glycogen Synthase Kinase 3 beta Multidisciplinary Behavior Animal Valproic Acid RNA-Binding Proteins Mood stabilizer medicine.disease Magnetic Resonance Imaging Facial Expression Mice Inbred C57BL Affect HEK293 Cells Mood Gene Expression Regulation PNAS Plus Schizophrenia Female Signal transduction Psychology Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences. 112 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1506491112 |
| Popis: | Inhibition of glycogen synthase kinase 3β (GSK3β) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3β affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3β. Phosphorylation of FXR1P by GSK3β is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3β and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3β gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3β/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3β also provides a mechanistic framework that may explain how inhibition of GSK3β can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role. |
| Databáze: | OpenAIRE |
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