title: Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway.
abstract: 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.
authors.affiliation: Department for Molecular Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Chandan
authors.initials: C
authors.lastname: Goswami
authors.forename: Julia
authors.initials: J
authors.lastname: Kuhn
authors.forename: Olayinka A
authors.initials: OA
authors.lastname: Dina
authors.forename: Gregorio
authors.initials: G
authors.lastname: Fernández-Ballester
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Tim
authors.initials: T
authors.lastname: Hucho
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology* / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology; D055785:Gene Knockdown Techniques; D015640:Ion Channel Gating; D008024:Ligands; D008297:Male; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D010146:Pain / Q000503:physiopathology; D010766:Phosphorylation; D011485:Protein Binding; D051744:Protein Kinase C-epsilon / Q000502:physiology; D011554:Pseudopodia / Q000648:ultrastructure; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; D004967:Estrogens; C520305:Gper1 protein, rat; D008024:Ligands; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014404:Tubulin; D004958:Estradiol; D051744:Protein Kinase C-epsilon