Compartmentalisation in cAMP signalling: A phase separation perspective

Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase‐mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid–liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase‐mediated degradation. Disrupting LLPS‐mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.