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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.