title: Induction of TRPV1 desensitization by a biased receptor agonist.
abstract: Selective suppression of hyperactive sensory neurons is an attractive strategy for managing pathological pain. Blocking Na(+) channels to eliminate action potentials and desensitizing transduction channels can both reduce sensory neuron excitability. The novel synthetic vanilloid ligand cap-ET preserves agonist activation of intracellular Ca(2+) signals and large organic cation transport but loses effective electric current induction. Cap-ET can therefore be used to deliver the membrane impermeable Na(+) channel blocker QX-314 to substantially inhibit voltage-activated Na(+) currents. We explored, besides facilitating entry of organic cationic therapeutics, whether cap-ET can also produce receptor desensitization similar to the natural agonist capsaicin. Using the YO-PRO-1 based fluorescent dye uptake assay, we found that cap-ET effectively triggered Ca(2+) dependent desensitization of TRPV1 when the receptor was pre-sensitized with the surrogate oxidative chemical phenylarsine oxide (PAO), suggesting an alternative use of permanently charged cationic capsaicinoids in differential neuronal silencing.
authors.affiliation: Cornell University, Ithaca, NY, USA.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Chuang
authors.forename: Huai-hu
authors.initials: HH
authors.lastname: Chuang
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D002211:Capsaicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D018689:Sensory System Agents / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D001152:Arsenicals; D004791:Enzyme Inhibitors; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C029341:oxophenylarsine; C012647:QX-314; D008012:Lidocaine; D002211:Capsaicin