Induction of TRPV1 desensitization by a biased receptor agonist

Channels (Austin). 2011 Nov-Dec;5(6):464-7. doi: 10.4161/chan.5.6.17401. Epub 2011 Nov 1.

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.

MeSH terms

  • Anesthetics, Local / pharmacology*
  • Animals
  • Arsenicals / pharmacology
  • Calcium Signaling / drug effects*
  • Calcium Signaling / genetics
  • Capsaicin / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Humans
  • Lidocaine / analogs & derivatives
  • Lidocaine / pharmacology
  • Sensory System Agents / pharmacology*
  • TRPV Cation Channels / agonists*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism

Substances

  • Anesthetics, Local
  • Arsenicals
  • Enzyme Inhibitors
  • Sensory System Agents
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • oxophenylarsine
  • QX-314
  • Lidocaine
  • Capsaicin