Mechanisms of endothelin-1-induced MAP kinase activation in adrenal glomerulosa cells

Abstract

G protein-coupled receptors (GPCRs) such as angiotensin II, bradykinin and endothelin-1 (ET-1) are critically involved in the regulation of adrenal function, including aldosterone production from zona glomerulosa cells. Whereas substantial data are available on the signaling mechanisms of ET-1 in cardiovascular tissues, such information in adrenal glomerulosa cells is lacking. Bovine adrenal glomerulosa (BAG) cells express receptors for endothelin-1 (ET-1) and their stimulation caused phosphorylation of Src (at Tyr416), proline-rich tyrosine kinase (Pyk2 at Tyr402), extracellularly regulated signal kinases (ERK1/2), and their dependent proteins, p90 ribosomal S6 kinase (RSK-1) and CREB. ET-1 elicited these responses predominantly through activation of a G i -linked cascade with a minor contribution from the G q /PKC pathway. Whereas selective inhibition of EGF-R kinase with AG1478 caused complete inhibition of EGF-induced ERK/ RSK-1/CREB activation, it caused only partial reduction (30-40%) of such ET-1-induced responses. Consistent with this, inhibition of matrix metalloproteinases (MMPs) with GM6001 reduced ERK1/2 activation by ET-1, consistent with partial involvement of the MMP-dependent EGF-R activation in this cascade. Activation of ERK/RSK-1/CREB by both ET-1 and EGF was abolished by inhibition of Src, indicating its central role in ET-1 signaling in BAG cells. Moreover, the signaling characteristics of ET-1 in cultured BAG cells closely resembled those observed in clonal adrenocortical H295R cells. The ET-1-induced proliferation of BAG and H295 R cells was much smaller than that induced by Ang II or FGF. These data demonstrate that ET-1 causes ERK/RSK-1/CREB phosphorylation predominantly through activation of G i and Src, with a minor contribution from MMP-dependent EGF-R transactivation.

Endothelin (ET)‐1 and ET‐3 promote expression ofc‐fosandc‐junin human choriocarcinoma via ETBreceptor‐mediated Gi‐ and Gq‐pathways and MAP kinase activation

“…Our findings on ET‐1‐ and ET‐3‐mediated G‐protein coupling in JAR and Jeg‐3 cells are supported by the observation that both choriocarcinoma cell lines lack the G → T missense mutation (Trp276Cys) within the human ET B receptor, and thus no impaired G αq signalling has been observed (Figure 4). Inhibition of p42/44 MAPK after treatment of cells with PP2 or manumycin A demonstrates involvement of the Src‐Ras/Raf pathway as previously shown for adrenal glomerulosa cells ( Shah et al ., 2006 ). Therefore, we propose that phosphorylation of p42/44 MAPK and subsequent expression of early responsive genes occurs along the signalling cascade, as shown in Figure 10.…”

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

“…ET A -mediated cell proliferation in zona glomerulosa cells within the perfused rat adrenal gland was dependent on tyrosine kinase (483). In bovine zona glomerulosa cells, ET-1 stimulates phosphorylation of src, Pyk2, ERK1/2, p90 ribosomal S6 kinase (RSK-1), and CREB (686). This occurred primarily through activation of a G i and to a lesser extent via G q ; PKC and matrix mellatoproteinase-dependent EGF-R transactivation were also involved.…”

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

“…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). Thus, we next explored a role for PLC and PKC in negative regulation of ENaC by ET-1.…”