CREB - A MAJOR MEDIATOR OF NEURONAL NEUROTROPHIN RESPONSES

Neurotrophins regulate neuronal survival, differentiation, and synapti c function. To understand how neurotrophins elicit such diverse respon ses, we elucidated signaling pathways by which brain-derived neurotrop hic factor (BDNF) activates gene expression in cultured neurons and hi ppocampal slices. We found, unexpectedly, that the transcription facto r cyclic AMP response element-binding protein (CREB) is an important r egulator of BDNF-induced gene expression. Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at least two signal ing pathways: by a calcium/calmodulin-dependent kinase IV (CaMKIV)-reg ulated pathway that is activated by the release of intracellular calci um and by a Ras-dependent pathway. These findings reveal a previously unrecognized, CaMK-dependent mechanism by which neurotrophins activate CREB and suggest that CREB plays a central role in mediating neurotro phin responses in neurons.