The neuroprotective agent, valproic acid, regulates the mitogen-activated protein kinase pathway through modulation of protein kinase A signalling in Dictyostelium discoideum

Eur J Cell Biol. 2006 Sep;85(9-10):1047-57. doi: 10.1016/j.ejcb.2006.04.013. Epub 2006 Jun 8.


Activation of the mitogen-activated protein kinase (MAPK) cascade gives rise to a neuroprotective effect in a variety of cell types. The bipolar disorder treatment, valproic acid (VPA), increases the activity of this pathway by modulating extracellular signal-regulated kinase 2 (ERK2) phosphorylation through an unknown mechanism. To investigate the molecular basis of this effect, we have used the biomedical model system Dictyostelium discoideum to dissect this signalling pathway. We find that, similar to mammalian systems, VPA causes a transient increase in the activation of the MAPK signalling pathway, as shown by ERK2 phosphorylation. We show that the MAP kinase and phosphatase, protein kinase A (PKA) and glycogen synthase kinase signalling pathways all function in controlling the levels of phospho-ERK2 (pERK2). We find that VPA induces elevated pERK2 levels through attenuation of the PKA signalling pathway. Interestingly, pERK2 levels are also controlled by another bipolar disorder drug, lithium, providing a common effect of these two drugs. This work therefore suggests a conserved pathway in eukaryotes that is targeted by neuroprotective and bipolar disorder drugs and allows us to propose a model for this neuroprotective effect.

Publication types

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

MeSH terms

  • Animals
  • Anticonvulsants / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dictyostelium / physiology*
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Fluorescence Resonance Energy Transfer
  • Glycogen Synthase Kinases / metabolism
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neuroprotective Agents / metabolism*
  • Protozoan Proteins / metabolism
  • Receptors, Cyclic AMP / metabolism
  • Valproic Acid / metabolism*


  • Anticonvulsants
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Protozoan Proteins
  • Receptors, Cyclic AMP
  • cyclic AMP receptor cAR1
  • Valproic Acid
  • Glycogen Synthase Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase Kinases