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

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