title: Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1.
abstract: Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. Inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling.
authors.affiliation: Functional Genomics Section, Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: Jason
authors.initials: J
authors.lastname: Keller
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Nitin
authors.initials: N
authors.lastname: Agarwal
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D020013:Calcium Signaling; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009619:Nociceptors / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry
chemical_list: D017931:DNA Primers; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013912:Threonine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse