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Depolarization-induced signaling to Ras, Rap1 and MAPKs in cortical neurons

Simona Baldassa1, Renata Zippel, Emmapaola Sturani

  • 1Department of Biomolecular Sciences and Biotechnology, University of Milan, via Celoria 26, 20133 Milan, Italy.

Brain Research. Molecular Brain Research
|November 5, 2003
PubMed

Insights

Membrane depolarization activates Ras and Rap1 signaling pathways in neurons. Protein kinase A is crucial for Rap1 activation and Erk stimulation, revealing new insights into neuronal signaling regulation.

Area of Science:

  • Neuroscience
  • Cellular signaling

Background:

  • Neuronal membrane depolarization initiates complex intracellular signaling cascades.
  • Key players include small GTPases Ras and Rap1, and mitogen-activated protein kinases (MAPKs) Erk1/2.

Purpose of the Study:

  • To investigate the intracellular signaling mechanisms regulating Ras, Rap1, and MAPK activation in mouse cortical neurons upon depolarization.
  • To elucidate the distinct roles of calmodulin and protein kinase A (PKA) in these pathways.

Main Methods:

  • Utilized mouse-cultured cortical neurons.
  • Examined GTP-loading of Ras and Rap1.
  • Assessed MAPK (Erk1/2) activation.
  • Employed pharmacological inhibitors (calmodulin blockade, genistein) and PKA activity modulation.

Main Results:

  • Depolarization induced rapid, strong Ras activation and slower, weaker Rap1 activation.
  • Calmodulin blockade impaired Ras/Rap1 GTP-loading and MAPK response.
  • PKA activity was essential for Rap1 activation and full Erk stimulation, but not Ras activation.
  • PKA-dependent Rap1 activation involved tyrosine kinases and was independent of Src family kinases.

Conclusions:

  • Differential kinetics of Ras and Rap1 activation observed in neurons.
  • Calmodulin and PKA play critical, distinct roles in regulating depolarization-induced signaling.
  • Identified a tyrosine kinase-dependent mechanism for PKA-mediated Rap1 activation in neurons.

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