Dopamine Induces a PI3-Kinase-Independent Activation of Akt in Striatal Neurons: A New Route to cAMP Response Element-Binding Protein Phosphorylation

Abstract

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 elementbinding 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.

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

“…This observation is also consistent with data obtained from DAT-KO mice in which DA receptors are continuously stimulated. In this regard, our results differ from previous reports of a D2 receptor activation of Akt and inactivation of GSK-3␤ after short-term exposure of cell cultures to DA agonists (40)(41)(42) or within 15 min after treatment of mice with cocaine (40) or amphetamine (43). Further detailed studies of DA receptor signaling at different time points after stimulation will be necessary to explain these discrepancies.…”

Transcriptional Control of Cholesterol Biosynthesis in Schwann Cells by Axonal Neuregulin 1

“…5c). It has been previously shown that CREB is a regulatory target for the protein kinase Akt (23)(24)(25)(26)(27). In this way we show that myr-Akt induces notably the activity of a CRE-luciferase reporter transfected to Schwann cells (Fig.…”

“…downstream target of Akt (22)(23)(24)(25)(26)(27). However, we also found that the deletion of the CRE in the HMGR reductase promoter did not reduce the myr-Akt-dependent transcriptional activity (Fig.…”

A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

“…Striata were dissected out from 14-d-old Swiss mouse embryos (Janvier, France) and prepared as previously described (Brami-Cherrier et al, 2002). Cells were suspended in Neurobasal medium supplemented with B27 (Invitrogen, Cergy Pontoise, France), 500 nM L-glutamine, 60 g/ml penicillin G and 25 M ␤-mercaptoethanol (Sigma, L'Isle d'Abeau, Chasnes, France) and plated into 24-well (1.8 ϫ 10 5 cells per well) or 6-well (8.6 ϫ 10 5 cells per well) Nunc (Dutscher, Brumath, France) multiwell plates coated with 50 g/ml poly-D-lysine (Sigma).…”