Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway

J Neurochem. 2011 Jun;117(6):995-1008. doi: 10.1111/j.1471-4159.2011.07270.x. Epub 2011 May 13.


Recently, we described estrogen and agonists of the G-protein coupled estrogen receptor GPR30 to induce protein kinase C (PKC)ε-dependent pain sensitization. PKCε phosphorylates the ion channel transient receptor potential, vanilloid subclass I (TRPV1) close to a novel microtubule-TRPV1 binding site. We now modeled the binding of tubulin to the TRPV1 C-terminus. The model suggests PKCε phosphorylation of TRPV1-S800 to abolish the tubulin-TRPV1 interaction. Indeed, in vitro PKCε phosphorylation of TRPV1 hindered tubulin-binding to TRPV1. In vivo, treatment of sensory neurons and F-11 cells with estrogen and the GPR30 agonist, G-1, resulted in microtubule destabilization and retraction of microtubules from filopodial structures. We found estrogen and G-1 to regulate the stability of the microtubular network via PKC phosphorylation of the PKCε-phosphorylation site TRPV1-S800. Microtubule disassembly was not, however, dependent on TRPV1 ion conductivity. TRPV1 knock-down in rats inverted the effect of the microtubule-modulating drugs, Taxol and Nocodazole, on estrogen-induced and PKCε-dependent mechanical pain sensitization. Thus, we suggest the C-terminus of TRPV1 to be a signaling intermediate downstream of estrogen and PKCε, regulating microtubule-stability and microtubule-dependent pain sensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line
  • Cyclopentanes / pharmacology
  • Estradiol / pharmacology*
  • Estrogens / pharmacology*
  • Estrogens / physiology
  • Ganglia, Spinal / cytology
  • Gene Knockdown Techniques
  • Ion Channel Gating
  • Ligands
  • Male
  • Microtubules / drug effects*
  • Microtubules / ultrastructure
  • Models, Molecular
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Pain / physiopathology
  • Phosphorylation
  • Protein Binding
  • Protein Kinase C-epsilon / physiology
  • Pseudopodia / ultrastructure
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists
  • Signal Transduction
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Tubulin / metabolism


  • 1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone
  • Cyclopentanes
  • Estrogens
  • Gper1 protein, rat
  • Ligands
  • Quinolines
  • Receptors, G-Protein-Coupled
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Tubulin
  • Estradiol
  • Protein Kinase C-epsilon