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Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

ABSTRACT: By screening a cDNA library derived from the A10 rat vascular smooth muscle cell line for functional expression in COS cells, we have isolated a high-affinity receptor for endothelin 1 (Kd = 476 pM) and endothelin 2. The affinity of the cloned endothelin receptor for endothelin 3 is greater than 100 times less in A10 cells and in a CHO cell line stably transformed by the endothelin receptor cDNA. The 426-amino acid receptor polypeptide has seven putative hydrophobic transmembrane domains and is presumed to be a member of the family of guanine nucleotide-binding regulatory (G) protein-coupled receptors. Microinjection of in vitro transcripts of the cloned cDNA into CHO cells confers a transient increase in intracellular calcium in response to endothelin 1, indicating that the receptor is functional and couples to the appropriate G protein(s). RNA analysis reveals high expression in rat lung and heart, tissues known to exhibit binding to iodinated endothelin 1.

SUBMITTER: Lin HY

PROVIDER: S-EPMC51410 | biostudies-other | 1991 Apr

REPOSITORIES: biostudies-other

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Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

Lin H Y HY Kaji E H EH Winkel G K GK Ives H E HE Lodish H F HF

Proceedings of the National Academy of Sciences of the United States of America 19910401 8

By screening a cDNA library derived from the A10 rat vascular smooth muscle cell line for functional expression in COS cells, we have isolated a high-affinity receptor for endothelin 1 (Kd = 476 pM) and endothelin 2. The affinity of the cloned endothelin receptor for endothelin 3 is greater than 100 times less in A10 cells and in a CHO cell line stably transformed by the endothelin receptor cDNA. The 426-amino acid receptor polypeptide has seven putative hydrophobic transmembrane domains and is ...[more]

PMID: 1849646

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Project description:AIMS:Peroxisome proliferator-activated receptor ? (PPAR?) agonists reduce blood pressure and vascular injury in hypertensive rodents. Ppar? inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar? gene in VSMC (smPpar?-/-) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS:eET-1, smPpar?-/- and eET-1/smPpar?-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPpar? inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPpar?-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPpar?-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPpar?-/-. Mesenteric artery reactive oxygen species increased in smPpar? and were further enhanced in eET-1/smPpar?-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPpar? and increased further in eET-1/smPpar?-/-. Spleen CD11b+ cells were increased in smPpar?-/- and further enhanced in eET-1/smPpar?-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPpar?-/- but not in eET-1/smPpar?-/-. Spleen T regulatory lymphocytes increased in smPpar? and decreased in eET-1, and decreased further in eET-1/smPpar?-/-. CONCLUSION:VSMC Ppar? inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPAR? in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPpar?-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

Dataset Information

Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

Publications

Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

Similar Datasets

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