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2 11.. SSuummmmaarryy The vanilloid receptor (TRPV1) plays a role of the polymodal detector of nociceptive stimuli in a subset of small and medium sized primary sensory neurons in mammals. This channel can be activated by vanilloid compounds, low pH, and noxious heat, and its function is modulated by a wide range of endogenous and exogenous agents. Our results demonstrate that the reducing agent dithiothreitol (DTT) strongly potentiates both the native and recombinant rat TRPV1 channel when applied at millimolar concentrations to the external solution under intact whole-cell conditions. Since the effects of DTT were almost immediate, dose-dependent, and reversible, the contribution of extracellular cysteine residues within the putative pore-loop region of TRPV1, Cys616, Cys621, and Cys634 has been proposed. We show that the chemical modification of TRPV1 by both reducing and oxidizing agents leads to an increased response to heat. In addition, we identify the extracellularly located cysteine at position 621 which contributes to the DTT-induced potentiation of heat-activated currents mediated by TRPV1. Our data also indicate that capsaicin concentration is radically altered by the presence of oxidizing agents. More generally, the redox-active substances can substantially affect the activity of TRPV1 channels... |
