Endothelin-1 potentiates capsaicin-induced TRPV1 currents via the endothelin A receptor.
Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to painful stimuli. The cellular mechanisms of the ET-1-mediated effects are only poorly understood. TRPV1, the heat-, proton-, and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released by painful stimuli and during inflammation, is a potential target for the action of ET-1. In immunocytochemistry of rat lumbar dorsal root ganglion using TRPV1- and ET(A) receptor-specific antibodies, both proteins were found to be co-expressed in small sensory neurons. To provide evidence that ET-1 can modulate TRPV1 activity via the ET(A) receptor, we used HEK 293 cells transiently co-expressing a fusion protein of TRPV1 and the yellow fluorescent protein (TRPV1-YFP) and the ET(A) receptor. In whole-cell patch clamp recordings of HEK293 cells co-expressing TRPV1-YFP and the ET(A) receptor, capsaicin (10 nM) elicited small currents, which were markedly potentiated when capsaicin (10 nM) and ET-1 (100 nM) were applied simultaneously. The data indicate that ET-1 potentiates TRPV1 activity via the ET(A) receptor and that this process is likely to play a crucial role in the pain-producing and pain-potentiating effects of ET-1. Thus, ET(A) receptor antagonists may be of importance in painful states with increased circulating ET-1 levels, as found in cancer and in chronic inflammation.
Plant
Tim D
TD
Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Germany.
Zöllner
Christian
C
Mousa
Shaaban A
SA
Oksche
Alexander
A
D002211:Capsaicin / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D018408:Patch-Clamp Techniques; D044022:Receptor, Endothelin A / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; D002211:Capsaicin