Transforming growth factor-β1 regulates Cdk5 activity in primary sensory neurons

J Biol Chem. 2012 May 11;287(20):16917-29. doi: 10.1074/jbc.M111.329979. Epub 2012 Mar 28.


In addition to many important roles for Cdk5 in brain development and synaptic function, we reported previously that Cdk5 regulates inflammatory pain signaling, partly through phosphorylation of transient receptor potential vanilloid 1 (TRPV1), an important Na(+)/Ca(2+) channel expressed in primary nociceptive afferent nerves. Because TGF-β regulates inflammatory processes and its receptor is expressed in TRPV1-positive afferents, we studied the cross-talk between these two pathways in sensory neurons during experimental peripheral inflammation. We demonstrate that TGF-β1 increases transcription and protein levels of the Cdk5 co-activator p35 through ERK1/2, resulting in an increase in Cdk5 activity in rat B104 neuroblastoma cells. Additionally, TGF-β1 enhances the capsaicin-induced Ca(2+) influx in cultured primary neurons from dorsal root ganglia (DRG). Importantly, Cdk5 activity was reduced in the trigeminal ganglia and DRG of 14-day-old TGF-β1 knock-out mice, resulting in reduced Cdk5-dependent phosphorylation of TRPV1. The decreased Cdk5 activity is associated with attenuated thermal hyperalgesia in TGF-β1 receptor conditional knock-out mice, where TGF-β signaling is significantly reduced in trigeminal ganglia and DRG. Collectively, our results indicate that active cross-talk between the TGF-β and Cdk5 pathways contributes to inflammatory pain signaling.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Ganglia, Spinal / metabolism*
  • Ganglia, Spinal / pathology
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Pain / genetics
  • Pain / metabolism
  • Pain / pathology
  • Phosphorylation / genetics
  • Rats
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / pathology
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Trigeminal Ganglion / metabolism*
  • Trigeminal Ganglion / pathology


  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Transforming Growth Factor beta1
  • Trpv1 protein, rat
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse
  • Cdk5 protein, rat
  • Mitogen-Activated Protein Kinase 3
  • Calcium