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TRPV1 is a nonselective cation channel activated by capsaicin, low pH and noxious heat, and plays a key role in nociception.Understanding mechanisms for functional modulation of TRPV1 has important implications.One characteristic of TRPV1 is that channel activity induced by either capsaicin or other activators can be sensitized or modulated by factors involving different cell signaling mechanisms.4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS) has long been used as chloride channel and anion transporter blocker.In this study, we describe a novel mechanism for modulation of TRPV1 function by DIDS and analogs.The perforated patch clamp technique was used to study the effects of DIDS and analogs on functional modulation of TRPV1 in adult rat dorsal root ganglion (DRG) neurons, and in HEK 293 cells.DIDS did not induce activation of TRPV1 per se but increased drastically the TRPV1 currents induced by either capsaicin or low pH.DIDS also blocked the tachyphylaxis of low pH-induced TRPV 1 currents.