Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):660-5. doi: 10.1073/pnas.0609916104. Epub 2006 Dec 28.

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.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Calcium Signaling
  • Cyclin-Dependent Kinase 5 / deficiency
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • DNA Primers / genetics
  • Ganglia, Spinal / metabolism
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Molecular Sequence Data
  • Nociceptors / metabolism*
  • Phosphorylation
  • Rats
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • TRPV Cation Channels / chemistry
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Threonine / chemistry

Substances

  • DNA Primers
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Threonine
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse