Thimerosal decreases TRPV1 activity by oxidation of extracellular sulfhydryl residues.
TRPV1, a receptor for capsaicin, plays a key role in mediating thermal and inflammatory pain. Because the modulation of ion channels by the cellular redox state is a significant determinant of channel function, we investigated the effects of sulfhydryl modification on the activity of TRPV1. Thimerosal, which oxidizes sulfhydryls, blocked the capsaicin-activated inward current (I(cap)) in cultured sensory neurons, in a reversible and dose-dependent manner, which was prevented by the co-application of the reducing agent, dithiothreitol. Among the three cysteine residues of TRPV1 that are exposed to the extracellular space, the oxidation-induced effect of thimerosal on I(cap) was blocked only by a point mutation at Cys621. These results suggest that the modification of an extracellular thiol group can alter the activity of TRPV1. Consequently, we propose that such a modulation of the redox state might regulate the physiological activity of TRPV1.
Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul 110-799, South Korea.
Yunju
Y
Jin
Dong Kwan
DK
Kim
Lee-Yong
LY
Khil
Uhtaek
U
Oh
Jun
J
Kim
Jiyeon
J
Kwak
D000818:Animals; D000831:Animals, Newborn; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005110:Extracellular Space / Q000187:drug effects*; D005727:Ganglia, Spinal / Q000166:cytology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D008958:Models, Molecular; D016296:Mutagenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011817:Rabbits; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism*; D016415:Sequence Alignment / Q000379:methods; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013552:Swine; D050916:TRPV Cation Channels; D013849:Thimerosal / Q000494:pharmacology*; D014162:Transfection
D007473:Ion Channels; D011955:Receptors, Drug; D013438:Sulfhydryl Compounds; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013849:Thimerosal; D002211:Capsaicin