Reducing agent dithiothreitol facilitates activity of the capsaicin receptor VR-1.
The vanilloid receptor subtype 1 (VR1) is expressed in a sub-population of small dorsal root ganglion (DRG) neurones in mammals and serves as the common transducer of the pain-producing signals, such as noxious heat, acids and capsaicin [Caterina et al., Nature 389 (1997) 816-824; Tominaga et al., Neuron 21 (1998) 531-543]. On the extracellular side, VR1 has three cysteine residues at positions 616, 621 and 634. Here we report that dithiothreitol (DTT) (2-60 mM), an agent that maintains -SH groups of cysteines in a reduced state, greatly facilitates membrane currents induced by noxious heat or capsaicin (1 microM) in cultured DRG neurones from the rat and in VR1-transfected HEK293 cells. The effects of DTT are concentration-dependent and fully reversible. We suggest that the ratio between free sulfhydryl groups and disulfide bonds of the cysteine residues of VR1 pre-sets sensitivity of primary nociceptors to algogens and may represent a new target for treating some pain states in humans.
Vyklický
L
L
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. lvykl@biomed.cas.cz
Lyfenko
A
A
Susánková
K
K
Teisinger
J
J
Vlachová
V
V
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D019163:Reducing Agents / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014162:Transfection
D011955:Receptors, Drug; D019163:Reducing Agents; D002211:Capsaicin; D004229:Dithiothreitol