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

Elias Utreras1, Jason Keller, Anita Terse

  • 1Functional Genomics Section, Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|March 28, 2012
PubMed

Insights

Transforming growth factor-beta (TGF-β) signaling interacts with cyclin-dependent kinase 5 (Cdk5) to regulate inflammatory pain. This cross-talk enhances pain signaling by increasing Cdk5 activity and transient receptor potential vanilloid 1 (TRPV1) phosphorylation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • Cyclin-dependent kinase 5 (Cdk5) plays crucial roles in neuronal development and function, including regulating inflammatory pain signaling via transient receptor potential vanilloid 1 (TRPV1) phosphorylation.
  • Transforming growth factor-beta (TGF-β) is implicated in inflammatory processes, and its receptor is present in TRPV1-positive afferents.

Purpose of the Study:

  • To investigate the cross-talk between TGF-β and Cdk5 pathways in sensory neurons during experimental peripheral inflammation.
  • To elucidate the molecular mechanisms underlying TGF-β-mediated regulation of Cdk5 activity and its impact on TRPV1 function and inflammatory pain.

Main Methods:

  • Utilized rat B104 neuroblastoma cells and cultured primary neurons from dorsal root ganglia (DRG).
  • Assessed the effects of TGF-β1 on p35 (Cdk5 co-activator) expression and Cdk5 activity via ERK1/2 signaling.
  • Measured capsaicin-induced Ca(2+) influx in cultured neurons.
  • Analyzed Cdk5 activity and TRPV1 phosphorylation in trigeminal ganglia and DRG of TGF-β1 knockout mice.
  • Evaluated thermal hyperalgesia in TGF-β receptor conditional knockout mice.

Main Results:

  • TGF-β1 treatment increased p35 transcription and protein levels through ERK1/2, leading to elevated Cdk5 activity in neuroblastoma cells.
  • TGF-β1 enhanced capsaicin-induced Ca(2+) influx in primary sensory neurons.
  • Cdk5 activity and Cdk5-dependent TRPV1 phosphorylation were reduced in TGF-β1 knockout mice.
  • Reduced Cdk5 activity correlated with attenuated thermal hyperalgesia in mice with diminished TGF-β signaling in DRG and trigeminal ganglia.

Conclusions:

  • TGF-β1 signaling positively regulates Cdk5 activity by increasing its co-activator p35.
  • This TGF-β1-induced increase in Cdk5 activity contributes to inflammatory pain sensitization, partly through enhanced TRPV1 phosphorylation.
  • Cross-talk between TGF-β and Cdk5 pathways is a significant mechanism in inflammatory pain signaling.

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