title: Modulation of thromboxane receptor activation in rat glomerular mesangial cells.
abstract: Rat glomerular mesangial cells were used to investigate mechanisms of thromboxane A2 (TxA2) receptor regulation in the kidney. Exposure of mesangial cells to the TxA2 agonist U-46619 for 10 min reduced subsequent TxA2-induced increases in inositol phosphates and intracellular Ca2+ levels by approximately 70%. This loss of receptor responsiveness could be blocked by the TxA2 receptor antagonist SQ-29548 and was reversible after removal of agonist from the incubation medium. Radioligand binding studies using the TxA2 agonist [125I]BOP suggested that exposure of mesangial cells to U-46619 for 10 min reduced TxA2 receptor responsiveness without a loss of receptor sites from plasma membrane fractions of the cell, although the density of mesangial cell TxA2 receptors was decreased by approximately 60% after more prolonged exposure of mesangial cells to thromboxane agonists. Both desensitization to U-46619 and loss of TxA2 binding sites could be attenuated by the protein kinase C (PKC) inhibitors staurosporine, sphingosine, or H-7, and TxA2 receptor responsiveness was reduced in cells incubated with phorbol esters before stimulation with thromboxane agonists. We conclude that 1) agonist-specific decreases in TxA2 receptor responsiveness may involve initial uncoupling of the receptor from its effector systems, followed by a loss of TxA2 receptor sites from plasma membrane fractions of the cell, and 2) PKC may be involved in these processes.
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: R F
authors.initials: RF
authors.lastname: Spurney
authors.forename: J P
authors.initials: JP
authors.lastname: Middleton
authors.forename: J R
authors.initials: JR
authors.lastname: Raymond
authors.forename: T M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D017482:Receptors, Thromboxane / Q000502:physiology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013931:Thromboxanes / Q000502:physiology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007295:Inositol Phosphates; D011450:Prostaglandin Endoperoxides, Synthetic; D047428:Protein Kinase Inhibitors; D017482:Receptors, Thromboxane; D013931:Thromboxanes; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D002118:Calcium