Cyclic adenosine monophosphate-Protein kinase A-cAMP response element-binding protein-Brain-derived neurotrophic factor signaling pathway (cAMP-PKA-CREB-BDNF) (cAMP-PKA-CREB-BDNF)

The Cyclic adenosine monophosphate-Protein kinase A-cAMP response element-binding protein-Brain-derived neurotrophic factor (cAMP-PKA-CREB-BDNF) signaling pathway is a fundamental intracellular cascade that regulates synaptic plasticity, neuronal survival, and cognitive function (Pittenger & Duman, 2008; PubMed: 18708142). The process is initiated by the production of the second messenger cAMP, which activates Protein Kinase A (PKA). Activated PKA then phosphorylates the transcription factor cAMP Response Element-Binding protein (CREB), which binds to promoter regions to drive the expression of neurotrophic factors, most notably Brain-Derived Neurotrophic Factor (BDNF) (Carlezon et al., 2005; PubMed: 15694330). BDNF plays a pivotal role in the maintenance of existing neurons and the growth of new synapses, making this pathway a central focus in neuropsychiatric research (Lu et al., 2013; PubMed: 23696251). Dysregulation of this axis is implicated in the pathogenesis of depression and various neurodegenerative conditions, where reduced BDNF levels are often observed (Dwivedi, 2009; PubMed: 19359672). Consequently, therapeutic strategies aimed at enhancing this pathway—such as phosphodiesterase inhibitors or direct receptor agonists—are being explored to treat mood disorders and cognitive decline (Zhang et al., 2018; PubMed: 29486312).

Other names

cAMP/PKA/CREB/BDNF axiscAMP-dependent neurotrophic signaling cascadeCREB-BDNF signaling pathway

Enhancement of this pathway is typically achieved by increasing intracellular cAMP levels through adenylate cyclase activation or phosphodiesterase (PDE) inhibition. Elevated cAMP activates Protein Kinase A (PKA), which phosphorylates the transcription factor CREB at Ser133. Phosphorylated CREB then binds to cAMP response elements (CRE) in the promoter region of the BDNF gene, inducing its transcription and subsequent protein synthesis to promote neuronal health and synaptic connectivity (StatPearls, 2023; NBK470256; Nibuya et al., 1996; PubMed: 8630702).