Protein kinase A–cAMP response element-binding protein–brain-derived neurotrophic factor signaling axis (PKA–CREB–BDNF axis) (PKA–CREB–BDNF axis)

The Protein kinase A–cAMP response element-binding protein–brain-derived neurotrophic factor (PKA–CREB–BDNF) signaling axis is a central intracellular pathway that governs neuronal survival, synaptic plasticity, and cognitive function [PubMed: 18297054]. The pathway is triggered by the secondary messenger cyclic adenosine monophosphate (cAMP), which activates PKA, leading to the phosphorylation of the transcription factor CREB [UniProt: P16220]. Once activated, CREB induces the transcription of the BDNF gene, a critical neurotrophin that supports the growth and maintenance of neurons and facilitates long-term potentiation (LTP) [Nature Reviews Neuroscience: 10.1038/nrn3335]. This axis is frequently downregulated in neurodegenerative diseases like Alzheimer's and psychiatric conditions such as major depressive disorder, making it a prime target for therapeutic intervention [PubMed: 25637334]. Drugs targeting this axis, such as phosphodiesterase (PDE) inhibitors or antidepressants, aim to increase cAMP levels or BDNF expression to restore neuroplasticity and alleviate cognitive or mood-related symptoms [PubChem: CID 5059].

Other names

cAMP/PKA/CREB/BDNF pathwayPKA-CREB-BDNF signaling pathwaycAMP-CREB-BDNF axisNeurotrophic signaling axis

The mechanism involves the cAMP-mediated activation of Protein Kinase A (PKA), which phosphorylates the transcription factor CREB at Ser133. This phosphorylation enables CREB to bind to cAMP response elements (CRE) in the BDNF promoter, inducing the expression of Brain-Derived Neurotrophic Factor (BDNF), which then activates TrkB receptors to promote synaptic plasticity and neuronal survival [PubMed: 10678122, 18297054].