PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5

Cell Rep. 2018 Nov 27;25(9):2470-2483.e8. doi: 10.1016/j.celrep.2018.11.005.


Protein kinase C (PKC)-dependent mechanisms promote synaptic function in the mature brain. However, the roles of PKC signaling during synapse development remain largely unknown. Investigating each brain-enriched PKC isoform in early neuronal development, we show that PKCε acutely and specifically reduces the number of dendritic spines, sites of eventual synapse formation on developing dendrites. This PKCε-mediated spine suppression is temporally restricted to immature neurons and mediated through the phosphorylation and activation of Ephexin5, a RhoA guanine nucleotide exchange factor (GEF) and inhibitor of hippocampal synapse formation. Our data suggest that PKCε acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCε, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCε plays seemingly opposing roles that depend on neuronal maturity.

Keywords: Ephexin5; PKCepsilon; RhoA; dendritic spines; development; hippocampus; phosphorylation.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Brain / metabolism
  • Cell Differentiation
  • Dendritic Spines / metabolism*
  • Enzyme Activation
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Hippocampus / metabolism
  • Humans
  • Isoenzymes / metabolism
  • Mice, Inbred C57BL
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase C-epsilon / chemistry
  • Protein Kinase C-epsilon / metabolism*
  • Signal Transduction
  • rhoA GTP-Binding Protein / metabolism


  • Guanine Nucleotide Exchange Factors
  • Isoenzymes
  • Phosphoserine
  • Protein Kinase C-alpha
  • Protein Kinase C-epsilon
  • rhoA GTP-Binding Protein