Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: A new route to cAMP response element-binding protein phosphorylation

K. Brami-Cherrier (1) , E. Valjent (1, 2) , M. Garcia , C. Pages (3) , R. A. Hipskind (4) , J. Caboche (1)

1 NPA - Neurobiologie des processus adaptatifs
2 Transduction du Signal et Plasticite Dans Le Systeme Nerveux
3 UR TSCF - Technologies et systèmes d'information pour les agrosystèmes
4 IGMM - Institut de Génétique Moléculaire de Montpellier

Akt is classically described as a prosurvival serine/threonine kinase activated in response to trophic factors. After activation by phosphoinositide 3-kinase (PI3-kinase), it can translocate to the nucleus where it promotes specific genetic programs by catalyzing phosphorylation of transcription factors. We report here that both dopamine (DA) D1 (SKF38393) and D2 (quinpirole) agonist treatments rapidly increase, in primary striatal neurons in culture, phosphorylation levels of Akt on Thr(308),a residue that is critically involved in its kinase activity. These treatments also activate the extracellular signal-regulated kinase (ERK) pathway in the same population of striatal neurons. Induction of active, phospho-Thr(308) Akt by dopamine D1 and D2 agonists is insensitive to wortmannin and thus PI3-kinase independent, in contrast to growth factor-induced Akt activity. D1- and D2-induced phospho-Thr(308) Akt is decreased by the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, as well as by overexpression of a dominant-negative version of MEK, thus implicating the Ras/ERK signaling cascade in this process. Furthermore, overexpression of a mutant form of Akt that cannot be activated impaired cAMP response element-binding protein (CREB) phosphorylation induced by SKF38393 and quinpirole treatments. Activation of Akt on Thr(308) was also found in vivo in striatal neurons after acute administration of cocaine, a psychostimulant that strongly increases DA transmission. Thus, multiple intracellular pathways can transduce signals from dopamine receptors to CREB in striatal neurons, one of these being Akt. We propose that this signaling pathway plays a pivotal role in DA-induced regulation of gene expression and long-term neuronal adaptation in the striatum.

Mots clés: extracellular signal-regulated kinase phospho-thr(308) akt pi3-kinase camp gene regulation nuclear translocation cocaine promotes cell-survival nerve growth-factor kinase-b transcription factor signaling pathway gene-expression phosphatidylinositol 3-kinase molecular mechanisms coupled receptors mitogen

Domaines: Biochimie, Biologie Moléculaire

K. Brami-Cherrier, E. Valjent, M. Garcia, C. Pages, R. A. Hipskind, et al.. Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: A new route to cAMP response element-binding protein phosphorylation. Journal of Neuroscience, 2002, 22 (20), pp.8911--8921. ⟨10.1523/JNEUROSCI.22-20-08911.2002⟩. ⟨hal-02197517⟩