Abstract
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.
Highlights
Cyclin-dependent kinase 5 (Cdk5) participates in the regulation of nociceptive signaling and peripheral inflammation increase its activity
We found that Transforming growth factor-1 (TGF-1) increases Cdk5 activity in B104 neuroblastoma cells and causes increased Cdk5-dependent transient receptor potential vanilloid 1 (TRPV1) phosphorylation and capsaicin-induced Ca2ϩ influx in dorsal root ganglia (DRG) primary cultures
TGF-1 Increased p35 Promoter Activity and p35 mRNA Levels in Rat B104 Neuroblastoma Cells—Previously, we discovered that the expression level of p35 is the limiting factor for Cdk5 activity [36]
Summary
Cdk participates in the regulation of nociceptive signaling and peripheral inflammation increase its activity. Conclusion: There is active cross-talk between TGF- and Cdk signaling pathways that affects pain. In addition to many important roles for Cdk in brain development and synaptic function, we reported previously that Cdk regulates inflammatory pain signaling, partly through phosphorylation of transient receptor potential vanilloid 1 (TRPV1), an important Na؉/Ca2؉ channel expressed in primary nociceptive afferent nerves. Because TGF- 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. Cdk activity was reduced in the trigeminal ganglia and DRG of 14-day-old TGF-1 knock-out mice, resulting in reduced Cdk5-dependent phosphorylation of TRPV1. Our results indicate that active cross-talk between the TGF- and Cdk pathways contributes to inflammatory pain signaling
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