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 Ca2+ 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. © 2011 Landes Bioscience.