cAMP-dependent signaling pathway (cAMP pathway)

The cAMP-dependent signaling pathway, also known as the adenylyl cyclase pathway, is a fundamental G protein-coupled receptor (GPCR)-triggered cascade that utilizes cyclic adenosine monophosphate (cAMP) as a second messenger to relay extracellular signals to intracellular effectors [1, 10]. Upon activation of a GPCR by a ligand, adenylyl cyclase is stimulated to convert ATP into cAMP, which then activates key downstream proteins such as protein kinase A (PKA), exchange proteins activated by cAMP (EPAC), and cyclic nucleotide-gated ion channels [1, 8, 11]. This pathway plays a critical role in regulating diverse biological processes, including nutrient metabolism, heart rate, immune cell function, and gene transcription via the phosphorylation of the cAMP response element-binding protein (CREB) [1, 3, 10]. Dysregulation of cAMP signaling is implicated in numerous pathologies, including various cancers, inflammatory conditions, and cardiovascular diseases [2, 8, 12]. Consequently, the pathway is a major focus of drug discovery, with therapeutic interventions ranging from phosphodiesterase (PDE) inhibitors that elevate cAMP levels to GPCR modulators that fine-tune the initiation of the cascade [5, 6, 7]. While highly effective, targeting this pathway presents challenges due to its widespread expression, which can lead to systemic side effects like gastrointestinal distress or cardiovascular issues [6, 7]. Ongoing research focuses on developing isoform-specific modulators to achieve more localized therapeutic effects and minimize off-target toxicity [5, 6].

Other names

Adenylyl cyclase pathwaycAMP-PKA signaling pathwaycAMP axisCyclic AMP signaling cascade

Drugs targeting this pathway typically act by modulating the levels of the second messenger cAMP through the activation or inhibition of adenylyl cyclases (AC) and phosphodiesterases (PDE), or by directly influencing downstream effectors like protein kinase A (PKA) and EPAC to alter cellular physiological responses [5, 6, 7].