CREB: a major mediator of neuronal neurotrophin responses

Neuron. 1997 Nov;19(5):1031-47. doi: 10.1016/s0896-6273(00)80395-5.


Neurotrophins regulate neuronal survival, differentiation, and synaptic function. To understand how neurotrophins elicit such diverse responses, we elucidated signaling pathways by which brain-derived neurotrophic factor (BDNF) activates gene expression in cultured neurons and hippocampal slices. We found, unexpectedly, that the transcription factor cyclic AMP response element-binding protein (CREB) is an important regulator of BDNF-induced gene expression. Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at least two signaling pathways: by a calcium/calmodulin-dependent kinase IV (CaMKIV)-regulated pathway that is activated by the release of intracellular calcium 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 neurotrophin responses in neurons.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Genes, ras / physiology
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Intracellular Membranes / metabolism
  • Nerve Growth Factors / physiology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Phosphorylation
  • Promoter Regions, Genetic / physiology
  • Rats
  • Ribosomal Protein S6 Kinases / physiology


  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Nerve Growth Factors
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium