In:
Molecular Pain, SAGE Publications, Vol. 3 ( 2007-01-01), p. 1744-8069-3-35-
Abstract:
Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to noxious stimuli, an effect probably mediated by the ET A receptor (ET A R) 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. Results: 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 A R. Specific 125 I-ET-1 binding sites (817 ± 92 fmol/mg) were detected in membrane preparations of DRG with an ET A R/ET B R ratio of 60:40. In an immunofluorescence analysis, coexpression of TRPV1 and the ET A R 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 A R. Weaker potentiation was observed in HEK293 cells coexpressing TRPV1 and the ET B R. ET A R 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 A R 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 A R-mediated potentiation. Conclusion: 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.
Type of Medium:
Online Resource
ISSN:
1744-8069
,
1744-8069
DOI:
10.1186/1744-8069-3-35
Language:
English
Publisher:
SAGE Publications
Publication Date:
2007
detail.hit.zdb_id:
2174252-2
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