Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: a new route to cAMP response element-binding protein phosphorylation.
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.
Brami-Cherrier
Karen
K
Laboratoire de Neurobiologie des Processus Adaptatifs, Centre National de la Recherche Scientifique/Université Pierre et Marie Curie, Unité Mixte de Recherche 7102, 75005 Paris, France.
Valjent
Emmanuel
E
Garcia
Marta
M
Pagès
Christiane
C
Hipskind
Robert A
RA
Caboche
Jocelyne
J
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005799:Genes, Dominant; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013347:Subcellular Fractions / Q000737:chemistry; D014162:Transfection
D003042:Cocaine; D017362:Cyclic AMP Response Element-Binding Protein; D004298:Dopamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2