title: Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons.
abstract: Although androgens induce numerous actions in brain, relatively little is known about which cell signaling pathways androgens activate in neurons. Recent work in our laboratory showed that the androgens testosterone and dihydrotestosterone (DHT) activate androgen receptor (AR)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling. Since the transcription factor cyclic AMP response element binding protein (CREB) is a downstream effector of MAPK/ERK and androgens activate CREB in non-neuronal cells, we investigated whether androgens activate CREB signaling in neurons. First, we observed that DHT rapidly activates CREB in cultured hippocampal neurons, as evidenced by CREB phosphorylation. Further, we observed that DHT-induced CREB phosphorylation is AR-dependent, as it occurs in PC12 cells stably transfected with AR but in neither wild-type nor empty vector-transfected cells. Next, we sought to identify the signal transduction pathways upstream of CREB phosphorylation using pharmacological inhibitors. DHT-induced CREB phosphorylation in neurons was found to be dependent upon protein kinase C (PKC) signaling but independent of MAPK/ERK, phosphatidylinositol 3-kinase, protein kinase A, and Ca(2+)/calmodulin-dependent protein kinase IV. These results demonstrate that DHT induces PKC-dependent CREB signaling, which may contribute to androgen-mediated neural functions.
authors.affiliation: Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Thuy-Vi V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Mingzhong
authors.initials: M
authors.lastname: Yao
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Pike
mesh_terms: D000704:Analysis of Variance; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection
chemical_list: D000728:Androgens; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases