PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis.
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.
Seino
Susumu
S
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. seino@med.kobe-u.ac.jp
Shibasaki
Tadao
T
D000200:Action Potentials; D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004702:Endocrine Glands / Q000502:physiology; D005088:Exocrine Glands / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000502:physiology
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases