| First Author | Del'Guidice T | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 33 | Pages | E4610-9 |
| PubMed ID | 26240334 | Mgi Jnum | J:332980 |
| Mgi Id | MGI:6868939 | Doi | 10.1073/pnas.1506491112 |
| Citation | Del'Guidice T, et al. (2015) FXR1P is a GSK3beta substrate regulating mood and emotion processing. Proc Natl Acad Sci U S A 112(33):E4610-9 |
| abstractText | Inhibition of glycogen synthase kinase 3beta (GSK3beta) 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 GSK3beta 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 GSK3beta. Phosphorylation of FXR1P by GSK3beta is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3beta 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 GSK3beta gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3beta/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3beta also provides a mechanistic framework that may explain how inhibition of GSK3beta 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. |
