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C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission.

ABSTRACT: The dimerization of the G protein-coupled receptors for endothelin-1 (ET-1), endothelin A receptor (ETA) and endolethin B receptor (ETB), is well established. However, the signaling consequences of the homodimerization and heterodimerization of ETA and ETB is not well understood. Here, we demonstrate that peptides derived from the C-termini of these receptors regulate the signaling capacity of ET-1. The C-termini of the ETA and ETB receptors are believed to consist of three ?-helices, which may serve as points of interaction between the receptors. The third ?-helix in the C-terminus is of particular interest because of its amphipathic nature. In a cell line expressing only the ETA receptor, expression of residues Y430-S442, representing the third helix of the ETB C-terminus, leads to a dramatic increase in the signaling induced by ET-1. In contrast, in a cell line containing only ETB , Y430-S442 has an antagonistic effect, slightly reducing the ET-1 induced signal. Computational docking results suggest that the ?-helical ETB -derived peptide binds to the second and third intracellular loops of the ETA receptor consistent with the alteration of its signaling capacity. Our results described here provide important insight into ETA /ETB receptor interactions and possibly a new approach to regulate specific G protein-coupled receptor signal transmission.

SUBMITTER: Yatawara A

PROVIDER: S-EPMC3770155 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission.

Yatawara Achani A Wilson Jamie L JL Taylor Linda L Polgar Peter P Mierke Dale F DF

Journal of peptide science : an official publication of the European Peptide Society 20130225 4

The dimerization of the G protein-coupled receptors for endothelin-1 (ET-1), endothelin A receptor (ETA) and endolethin B receptor (ETB), is well established. However, the signaling consequences of the homodimerization and heterodimerization of ETA and ETB is not well understood. Here, we demonstrate that peptides derived from the C-termini of these receptors regulate the signaling capacity of ET-1. The C-termini of the ETA and ETB receptors are believed to consist of three α-helices, which may ...[more]

PMID: 23436727

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Project description:BACKGROUND AND PURPOSE: Mechanisms associated with the enhanced contractile response to endothelin-1 in hyperinsulinaemic diabetes have been examined using the rat aorta. Functions for angiotensin II, endothelin-1 receptor expression and extracellular signal-regulated kinase (ERK) have been investigated. EXPERIMENTAL APPROACH: Streptozotocin-induced diabetic rats were infused with angiotensin II or, following insulin treatment, were treated with losartan, an angiotensin II receptor antagonist. Contractions of aortic strips with or without endothelium, in response to endothelin-1 and angiotensin II, were examined in vitro. Aortic ET(A) receptors and ERK/MEK expression were measured by western blotting. KEY RESULTS: Insulin-treated diabetic rats exhibited increases in plasma insulin, angiotensin II and endothelin-1. The systolic blood pressure and endothelin-1-induced contractile responses in aortae in vitro were enhanced in insulin-treated diabetic rats and blunted by chronic losartan administration. LY294002 (phosphatidylinositol 3-kinase inhibitor) and/or PD98059 (MEK inhibitor) diminished the enhanced contractile response to endothelin-1 in aortae from insulin-treated diabetic rats. ET(A) and ET(B) receptors, ERK-1/2 and MEK-1/2 protein expression and endothelin-1-stimulated ERK phosphorylation were all increased in aortae from insulin-treated diabetic rats. Such increases were blunted by chronic losartan administration. Endothelin-1-induced contraction was significantly higher in aortae from angiotensin II-infused diabetic rats. angiotensin II-infusion increased ERK phosphorylation, but the expression of endothelin receptors and ERK/MEK proteins remained unchanged. CONCLUSIONS AND IMPLICATIONS: These results suggest that the combination of high plasma angiotensin II and insulin with a diabetic state induced enhancement of endothelin-1-induced vasoconstriction, ET(A) receptor expression and ERK expression/activity in the aorta. Losartan improved both the diabetes-related abnormalities and the diabetic hypertension.

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C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission.

Publications

C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission.

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