Cyclic AMP is the canonical Gs-coupled second messenger. Adenylate cyclase converts ATP → cAMP on Gs activation; cAMP activates PKA (protein kinase A) → phosphorylates downstream targets (CREB transcription factor, voltage-gated Ca²⁺ channels, ion pumps, contractile proteins, lipases). cAMP is degraded by phosphodiesterases (PDE1-11 isoforms): PDE3 in cardiac + smooth muscle (cilostazol target); PDE4 in inflammatory cells (apremilast, roflumilast targets); PDE5 in vascular + cavernosal smooth muscle (own pathway pde5_no_cgmp_axis — cGMP-specific). Many Rx classes converge here as Gs-coupled receptor agonists: β-agonists, glucagon, GLP-1 agonists, PTH analogs (intermittent pulse), calcitonin, V2 vasopressin. Caffeine + theophylline raise cAMP indirectly via non-selective PDE inhibition + adenosine antagonism. This integrative pathway is mostly for pathway-convergence detection — "any Gs-coupled or PDE-modulating drug" pile-on shows up here.
Organ Systems
cardiovascular
endocrine
nervous
Pathway Steps
gs-coupled-receptor-activation → adenylate-cyclase-activation — via Gαs binds + activates membrane AC1-9 isoforms → ATP → cAMP. Many hormones and neurotransmitters act through Gs-coupled receptors, whose activated Gαs subunit stimulates adenylate cyclase. This is the canonical start of cAMP signaling — the step locked on by cholera toxin and opposed by Gi-coupled receptors, so the cell’s cAMP level reflects a balance of inputs.
adenylate-cyclase-activation → pka-activation — via cAMP binds regulatory subunits → releases catalytic PKA subunits. Adenylate cyclase converts ATP to the second messenger cAMP, which rises rapidly and is degraded by phosphodiesterases (PDEs). cAMP’s main effector is protein kinase A: cAMP binding to PKA’s regulatory subunits frees the active catalytic subunits. PDE inhibitors (caffeine, the sildenafil class) act by raising cyclic-nucleotide levels here.
pka-activation → creb-phosphorylation — via PKA phosphorylates Ser133 of CREB → transcription of cAMP-responsive genes. Active PKA phosphorylates many targets, including the transcription factor CREB (Ser133), which recruits CBP/p300 to drive cAMP-responsive genes. This is how a transient membrane signal reaches the nucleus to change gene expression — and AKAP scaffolds localize PKA to give the signaling spatial specificity.
adenylate-cyclase-activation → cAMP degraded by phosphodiesterase (signal termination) — via PDE3/4 hydrolyze cAMP → 5′-AMP; PDE inhibitors preserve cAMP. The signal is switched off by phosphodiesterases (PDEs), which hydrolyze cAMP back to 5′-AMP — setting the duration and amplitude of the response. This off-switch is itself a major drug target: PDE inhibitors (caffeine/theophylline non-selectively, milrinone PDE3, apremilast/roflumilast PDE4) raise cAMP by blocking its degradation.
Known Modulators
caffeine (inhibitor) — PDE (non-selective) + adenosine A1/A2A antagonism. methylxanthine; raises cAMP via PDE inhibition + indirectly via removing adenosine-mediated AC inhibition; cross-link: caffeine_demethylation