title: Transforming growth factor-β1 regulates Cdk5 activity in primary sensory neurons.
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.
authors.affiliation: Functional Genomics Section, Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Utreras
authors.forename: Jason
authors.initials: J
authors.lastname: Keller
authors.forename: Anita
authors.initials: A
authors.lastname: Terse
authors.forename: Michaela
authors.initials: M
authors.lastname: Prochazkova
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000378:metabolism* / Q000473:pathology
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D053773:Transforming Growth Factor beta1; C493922:Trpv1 protein, rat; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium