Selective Phosphorylation of Nuclear CREB by Fluoxetine is Linked to Activation of CaM Kinase IV and MAP Kinase Cascades
Articolo
Data di Pubblicazione:
2004
Citazione:
Selective Phosphorylation of Nuclear CREB by Fluoxetine is Linked to Activation of CaM Kinase IV and MAP Kinase Cascades / E. Tiraboschi, D. Tardito, J. Kasahara, S. Moraschi, P. Pruneri, M. Gennarelli, G. Racagni, M. Popoli. - In: NEUROPSYCHOPHARMACOLOGY. - ISSN 0893-133X. - 29:10(2004), pp. 1831-1840.
Abstract:
Regulation of gene expression is purported as a major component in the long-term action of antidepressants. The transcription factor
cAMP-response element-binding protein (CREB) is activated by chronic antidepressant treatments, although a number of studies
reported different effects on CREB, depending on drug types used and brain areas investigated. Furthermore, little is known as to what
signaling cascades are responsible for CREB activation, although cAMP-protein kinase A (PKA) cascade was suggested to be a central
player. We investigated how different drugs (fluoxetine (FLX), desipramine (DMI), reboxetine (RBX)) affect CREB expression and
phosphorylation of Ser133 in the hippocampus and prefrontal/frontal cortex (PFCX). Acute treatments did not induce changes in these
mechanisms. Chronic FLX increased nuclear phospho-CREB (pCREB) far more markedly than pronoradrenergic drugs, particularly in
PFCX. We investigated the function of the main signaling cascades that were shown to phosphorylate and regulate CREB. PKA did not
seem to account for the selective increase of pCREB induced by FLX. All drug treatments markedly increased the enzymatic activity of
nuclear Ca2þ/calmodulin (CaM) kinase IV (CaMKIV), a major neuronal CREB kinase, in PFCX. Activation of this kinase was due to
increased phosphorylation of the activatory residue Thr196, with no major changes in the expression levels of a- and b-CaM kinase kinase,
enzymes that phosphorylate CaMKIV. Again in PFCX, FLX selectively increased the expression level of MAP kinases Erk1/2, without
affecting their phosphorylation. Our results show that FLX exerts a more marked effect on CREB phosphorylation and suggest that
CaMKIV and MAP kinase cascades are involved in this effect.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
antidepressant ; CREB ; CaM kinase IV ; MAP kinase ; cAMP-dependent protein kinase ; neuroplasticity
Elenco autori:
E. Tiraboschi, D. Tardito, J. Kasahara, S. Moraschi, P. Pruneri, M. Gennarelli, G. Racagni, M. Popoli
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