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TRPV1 function is modulated by Cdk5-mediated phosphorylation: insights into the molecular mechanism of nociception

Thomas Jendryke1, Michaela Prochazkova2, Bradford E Hall2

  • 1Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.

Scientific Reports
|February 24, 2016
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) phosphorylation of the TRPV1 channel at T406 significantly impacts pain perception. This molecular switch alters receptor function, affecting pain sensitivity and related behaviors.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • Transient Receptor Potential Vanilloid 1 (TRPV1) is a crucial ion channel in pain signaling.
  • Kinase-mediated phosphorylation regulates TRPV1 function, influencing pain states like hyperalgesia and allodynia.

Purpose of the Study:

  • To investigate the role of Cyclin-dependent kinase 5 (Cdk5) in modulating TRPV1 channel activity.
  • To elucidate the molecular and structural consequences of Cdk5-mediated phosphorylation at threonine-406 (T406) of TRPV1.

Main Methods:

  • Utilized genetically engineered mice with altered Cdk5 activity to assess TRPV1-mediated pain perception.
  • Generated and functionally characterized recombinant TRPV1 variants mimicking T406 phosphorylation states.
  • Employed electrophysiological recordings (whole-cell, single-channel) and Ca(2+) imaging to analyze receptor function.

Main Results:

  • Cdk5-mediated phosphorylation of TRPV1 at T406 critically affects ligand sensitivity, activation, desensitization kinetics, and voltage dependence.
  • Altering Cdk5 activity in vivo led to significant changes in pain sensitivity and capsaicin consumption.
  • Phosphorylation at T406 induces conformational changes influencing TRPV1 gating.

Conclusions:

  • T406 phosphorylation acts as a key molecular switch regulating TRPV1 channel function.
  • Cdk5-mediated phosphorylation of TRPV1 is a significant modulator of pain perception and behavior.
  • Understanding this mechanism offers potential therapeutic targets for pain management.

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