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Compartmentalisation in cAMP signalling: A phase separation perspective.

Milda Folkmanaite1, Manuela Zaccolo1

  • 1Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, UK.

British Journal of Pharmacology
|July 28, 2025
PubMed
Summary

Liquid-liquid phase separation (LLPS) dynamically organizes cyclic AMP (cAMP) and protein kinase A (PKA) signaling. This process compartmentalizes signaling, ensuring functional specificity and impacting cellular responses, with implications for diseases like cancer.

Keywords:
PKAcAMPcompartmentalisationliquid–liquid phase separationsignalling

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Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Signaling

Background:

  • Cells require precise spatiotemporal control of signaling pathways for functional specificity.
  • Compartmentalization of cyclic AMP (cAMP) and protein kinase A (PKA) signaling is crucial for distinct cellular responses.
  • Traditional mechanisms include PKA anchoring, phosphodiesterase activity, and restricted cAMP diffusion.

Purpose of the Study:

  • To review the emerging evidence for liquid-liquid phase separation (LLPS) in organizing cAMP signaling.
  • To highlight the role of LLPS in spatial restriction and functional specificity of cAMP/PKA pathways.
  • To discuss the physiological relevance and disease implications of LLPS in cAMP signaling.

Main Methods:

  • Literature review of current research on LLPS in cAMP signaling.
  • Analysis of studies implicating LLPS in receptor clustering, nucleotide synthesis, and effector activation.
  • Examination of evidence linking PKA RIα condensates to cAMP reservoirs and phosphodiesterase modulation.

Main Results:

  • LLPS offers a dynamic mechanism for spatially restricting cAMP activity within the cell.
  • PKA RIα condensates function as cAMP reservoirs, influencing local availability and degradation.
  • LLPS is implicated in various stages of cAMP signaling, from synthesis to termination.

Conclusions:

  • LLPS is a significant mechanism for cAMP signaling compartmentalization, complementing traditional models.
  • Disruption of LLPS in cAMP/PKA pathways is associated with diseases like cancer and neurodegeneration.
  • Understanding LLPS in cAMP signaling is vital for elucidating cellular function and disease pathogenesis.