Endothelin (ET)‐1 and ET‐3 promote expression ofc‐fosandc‐junin human choriocarcinoma via ET_Breceptor‐mediated G_i‐ and G_q‐pathways and MAP kinase activation

Abstract

Background and purpose: Endothelins (ETs) and their G protein-coupled receptors exert key physiological functions during normal and aberrant placental development. Trophoblast cells mediate the contact between the embryo and the mother, by establishing a transient organ, the placenta. Choriocarcinoma cells display many of the biochemical and morphological characteristics of in utero invasive trophoblast cells and may therefore be used as a suitable model to study epithelial tumour progression of foetal-derived cells. Experimental approach: The present study aimed at investigating ET receptor-mediated activation of the mitogen-activated protein kinase (MAPK) pathway in human choriocarcinoma. Key results: Both JAR and Jeg-3 choriocarcinoma cell lines expressed ET receptor subtype B (ET B ) but not ET A receptor transcripts. ET B receptor engagement by ET-1 and ET-3 resulted in a similar time-and concentration-dependent phosphorylation of p42/44 MAPK, also known as extracellular regulated kinase 1/2. Using specific pharmacological antagonists/inhibitors, we showed that ET-1/-3-mediated signal transduction by the ET B receptor is transmitted via G i -and G q -dependent pathways through activation of the Src (G i ) and protein kinase C (G q ) axis that converge at Ras/Raf, leading to downstream activation of p42/44. On a functional level, ET B engagement and subsequent phosphorylation of p42/44 resulted in enhanced transcription of the immediate early response genes c-fos and c-jun, a process commonly assumed to be mediated by the ET A receptor, and increased cell growth and relative cell area. Conclusions and implications: As human choriocarcinoma cells secrete ETs, pharmacological antagonism of ETs and/or ET B receptor-mediated signal transduction could represent a likely target therapy for choriocarcinoma.

Regulation of the epithelial Na+channel by endothelin-1 in rat collecting duct

“…Similar to stimulating src kinases, ET-1 signaling is also recognized to activate MAPK1/2 signaling in many types of cells, including epithelial cells. This ET-1-dependent stimulation of MAPK1/2 is src kinase dependent (11,24,28,39,40,52). The current results place MAPK1/2 signaling between src kinases and ENaC during ET-1 regulation.…”

“…Our rationale is that ET B receptors are G protein-coupled receptors capable of interacting with both G q and G i . ET-1 signaling through either of these G proteins can ultimately activate src tyrosine kinases in many different types of cells, including epithelial cells (11,24,39). However, ET-1 activation of PLC and PKC is critical to stimulating src kinases in response to G q but not G i signaling.…”

“…Activation of c-src by ET-1 via ET B is known to stimulate MAPK1/2 signaling in epithelial cells (28,39). Thus, we next tested a role for MAPK1/2 signaling in regulation of ENaC by ET-1 in collecting duct principal cells.…”

“…ET-1 decreases ENaC open probability via src family kinases. Endothelin receptors, including ET B , are coupled to G proteins and belong to the GPCR superfamily (11,24,39). ET B , through its cognate G protein alpha subunits (G q and G i ), activates a number of signaling cascades, including those mediated by PLC/PKC and src family tyrosine kinases (11,24,28,39,40,43,52,54).…”

Protective Effect Of Bosentan In Experimental Cerebral Ischemia-Reperfusion Injury

“…Yapılan bazı çalışmalarda endotelin 1 (ET1) seviyelerindeki artışın inflamatuar süreçler, ateroskleroz ve hipertansiyonda aşırı NO ve ONOOperoxynitrite üretimine sebep olduğu ve antioksidan düzeylerinde azalmalar meydana getirdiği gösterilmiştir (21)(22)(23) serbest oksijen radikalleri oluştuğu gösterilmiştir (24).…”