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

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons50170

Goswami,  C.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Goswami, C., Kuhn, J., Dina, O. A., Fernandez-Ballester, G., Levine, J. D., Ferrer-Montiel, A., et al. (2011). Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway. J Neurochem, 117(6), 995-1008. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21480900 http://onlinelibrary.wiley.com/store/10.1111/j.1471-4159.2011.07270.x/asset/j.1471-4159.2011.07270.x.pdf?v=1&t=gywolx5y&s=5f0e2096b13e079aca34c1461ef3938e570ce1e2.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-7950-3
Abstract
Recently, we described estrogen and agonists of the G-protein coupled estrogen receptor GPR30 to induce protein kinase C (PKC)epsilon-dependent pain sensitization. PKCepsilon 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 PKCepsilon phosphorylation of TRPV1-S800 to abolish the tubulin-TRPV1 interaction. Indeed, in vitro PKCepsilon 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 PKCepsilon-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 PKCepsilon-dependent mechanical pain sensitization. Thus, we suggest the C-terminus of TRPV1 to be a signaling intermediate downstream of estrogen and PKCepsilon, regulating microtubule-stability and microtubule-dependent pain sensitization.