Role of phosphatidylinositide 3-kinase in brain-derived neurotrophic factor-induced DARPP-32 expression in medium size spiny neurons in vitro.
Brain-derived neurotrophic factor (BDNF) regulates several properties of striatal dopaminoceptive medium-sized spiny neurons (MSNs) in vivo and in vitro, including expression levels of DARPP-32 (dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa). DARPP-32 is expressed in 96% of the MSNs, and is a key modulator of dopamine actions. We investigated the intracellular signal transduction pathways activated by BDNF in MSNs and via which BDNF induces DARPP-32 expression. We found that phosphorylation of the cyclic AMP response element binding protein (CREB) is only transiently increased following stimulation of MSNs by BDNF, whereas increased phosphorylation of the extracellular signal regulated kinases 1 and 2 (Erk1/2) and Akt is sustained for longer than 4 h. Treatment of cultures with inhibitors of mitogen-activated protein kinase kinase (MEK) or phosphatidylinositide 3-kinase (PI3K) showed that the majority of the BDNF-induced increase in DARPP-32 requires the PI3K pathway. We also found that inhibition of PI3K reduces BDNF-induced Erk phosphorylation, indicating that cross-talk between these pathways may play a prominent role in MSNs.
Stroppolo
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The Nathan Kline Institute, Orangeburg, New York 10962, USA.
Guinea
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Tian
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Sommer
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Ehrlich
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ME
D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D048429:Cell Size; D002867:Chromones / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000096:biosynthesis*; D010766:Phosphorylation; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one