PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis

Physiol Rev. 2005 Oct;85(4):1303-42. doi: 10.1152/physrev.00001.2005.


Stimulus-secretion coupling is an essential process in secretory cells in which regulated exocytosis occurs, including neuronal, neuroendocrine, endocrine, and exocrine cells. While an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) is the principal signal, other intracellular signals also are important in regulated exocytosis. In particular, the cAMP signaling system is well known to regulate and modulate exocytosis in a variety of secretory cells. Until recently, it was generally thought that the effects of cAMP in regulated exocytosis are mediated by activation of cAMP-dependent protein kinase (PKA), a major cAMP target, followed by phosphorylation of the relevant proteins. Although the involvement of PKA-independent mechanisms has been suggested in cAMP-regulated exocytosis by pharmacological approaches, the molecular mechanisms are unknown. Newly discovered cAMP-GEF/Epac, which belongs to the cAMP-binding protein family, exhibits guanine nucleotide exchange factor activities and exerts diverse effects on cellular functions including hormone/transmitter secretion, cell adhesion, and intracellular Ca(2+) mobilization. cAMP-GEF/Epac mediates the PKA-independent effects on cAMP-regulated exocytosis. Thus cAMP regulates and modulates exocytosis by coordinating both PKA-dependent and PKA-independent mechanisms. Localization of cAMP within intracellular compartments (cAMP compartmentation or compartmentalization) may be a key mechanism underlying the distinct effects of cAMP in different domains of the cell.

Publication types

  • Review

MeSH terms

  • Action Potentials
  • Animals
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / physiology*
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Endocrine Glands / physiology
  • Exocrine Glands / physiology
  • Exocytosis / physiology*
  • Humans
  • Neurons / physiology


  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases