title: Phenylarsine oxide as a redox modulator of transient receptor potential vanilloid type 1 channel function.
abstract: Transient receptor potential vanilloid type 1 (TRPV1) channels are capable of detecting and integrating noxious stimuli and play an important role in nociceptor activation and sensitization. It has been demonstrated that oxidizing agents are capable of positively modulating (sensitizing) the TRPV1 channel. The present study investigates the ability of the thiol-oxidizing agent phenylarsine oxide (PAO) to modulate TRPV1 currents under voltage-clamp conditions. We assessed the ability of PAO to modulate both proton- and capsaicin-activated currents mediated by recombinant human TRPV1 channels as well as native rat and human TRPV1 channels in dorsal root ganglion (DRG) neurons. Experiments with other oxidizing and reducing agents having various membrane-permeating properties supported the intracellular oxidizing mechanism of PAO modulation. The PAO modulation of proton-activated currents was consistent across the cell types studied, with an increase in current across the proton concentrations studied. PAO modulation of the capsaicin-activated current in hTRPV1/Chinese hamster ovary cells consisted of potentiation of the current elicited with low capsaicin concentrations and inhibition of the current at higher concentrations. This same effect was seen with these recombinant cells in calcium imaging experiments and with native TRPV1 channels in rat DRG neurons. Contrary to this, currents in human DRG neurons were potentiated at all capsaicin concentrations tested after PAO treatment. These results could indicate important differences in the reduction-oxidation modulation of human TRPV1 channels in a native cellular environment.
authors.affiliation: Discovery Research, Purdue Pharma LP, Cranbury, New Jersey.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Carlin
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Aniket
authors.initials: A
authors.lastname: Patel
authors.forename: Gregg
authors.initials: G
authors.lastname: Crumley
authors.forename: Victor I
authors.initials: VI
authors.lastname: Ilyin
mesh_terms: D000328:Adult; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D004791:Enzyme Inhibitors; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C029341:oxophenylarsine; D002211:Capsaicin; D002118:Calcium
keywords: capsaicin; human DRG; pain; rat DRG; sensitization