Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to noxious stimuli, an effect probably mediated by the ET_A receptor (ET_AR) expressed in sensory neurons. The cellular mechanisms of this ET-1-mediated effect are only poorly understood. TRPV1, the heat-, pH- and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released in response to noxious stimuli and during inflammation, is a potential target for the action of ET-1.

We studied the effects of ET-1 on TRPV1 in sensory neurons from the dorsal root ganglion (DRG) and in HEK293 cells coexpressing TRPV1 and the ET_AR. Specific ¹²⁵I-ET-1 binding sites (817 ± 92 fmol/mg) were detected in membrane preparations of DRG with an ET_AR/ET_BR ratio of 60:40. In an immunofluorescence analysis, coexpression of TRPV1 and the ET_AR was found in a subpopulation of primary sensory neurons. ET-1 strongly potentiated capsaicin-induced TRPV1 currents in some neurons, and in HEK293 cells co-expressing TRPV1 and the ET_AR. Weaker potentiation was observed in HEK293 cells coexpressing TRPV1 and the ET_BR. ET_AR activation also increased responses to low pH and heat. In HEK293 cells, strong potentiation of TRPV1 like that induced by ET-1 via the ET_AR could be induced by PKC activation, but not with activators of the adenylyl cyclase or the PKA pathway. Furthermore, inhibition of PKC with bisindolylmaleimide X (BIM X) or mutation of the PKC phosphorylation site S800 completely prevented ET_AR-mediated potentiation.

We conclude that ET-1 potentiates TRPV1 by a PKC-dependent mechanism and that this could play a major role in the algogenic and hyperalgesic effects of ET-1 described in previous studies.