Cyclic AMP synergistically enhances neuregulin-dependent ERK and Akt activation and cell cycle progression in Schwann cells

Glia. 2006 Apr 15;53(6):649-59. doi: 10.1002/glia.20330.


The elevation of intracellular cAMP synergistically enhances the neuregulin-dependent proliferation of cultured Schwann cells (SCs); however, the mechanism by which this occurs has not been completely defined. To better understand this mechanism, we investigated the effect of cAMP on the activation of the extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)-Akt (PKB) pathways by heregulin, a member of the neuregulin family. Using primary cultures of adult SCs, we demonstrated that the adenylyl cyclase activator, forskolin, enhanced heregulin-dependent SC proliferation by reducing the time required for S-phase entry. When cAMP levels were increased, using either forskolin or a cell permeable analogue of cAMP, the heregulin-induced phosphorylation of ERK was converted from transient to sustained and the heregulin-induced phosphorylation of Akt was synergistically increased. Consistent with these observations, studies in which inhibitors of MEK, the upstream stimulating ERK kinase, and PI3-K were administered at different times following the onset of stimulation indicated that sustained high levels of both MEK/ERK and PI3-K/Akt activity before S-phase initiation were essential for S-phase entry. Overall, these novel results indicate that in neuregulin-stimulated SCs the activation of cAMP-mediated pathways accelerates G1-S progression by prolonging ERK activation and concurrently enhancing Akt activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / drug effects
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • Cyclic AMP / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • G1 Phase / drug effects
  • G1 Phase / physiology
  • Genes, cdc / drug effects
  • Genes, cdc / physiology
  • Humans
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / enzymology
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism*
  • Neuregulin-1
  • Oncogene Protein v-akt / drug effects
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Rats
  • S Phase / drug effects
  • S Phase / physiology
  • Schwann Cells / drug effects
  • Schwann Cells / enzymology*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Enzyme Inhibitors
  • NRG1 protein, human
  • Nerve Tissue Proteins
  • Neuregulin-1
  • Colforsin
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Adenylyl Cyclases