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PAIN

Endothelin-1 Potentiates Capsaicin-Induced TRPV1 Currents Via the Endothelin A Receptor

Tim D. Plant^*, Christian Zöllner, Shaaban A. Mousa and Alexander Oksche^,1

^* Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Karl-von-Frisch Str. 1, 35033 Marburg, Germany; Klinik für Anästhesiologie und operative Intensivmedizin, Charité–Universitätsmedizin Berlin, Campus Benjamin-Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; and the Institut für Pharmakologie, Charité–Universitätsmedizin Berlin, Campus Benjamin-Franklin, Thielallee 67-73, 14195 Berlin-Dahlem, Germany

To whom requests for reprints should be addressed at ¹ Institut für Pharmakologie, Charité–Universitätsmedizin Berlin, Campus Benjamin-Franklin, Thielallee 67-73, 14195 Berlin-Dahlem. E-mail: alexander.oksche{at}charite.de

Abstract

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.

Key Words: G protein–coupled receptor • TRP channel • capsaicin • immunohistochemistry