Characterization of rat glomerular thromboxane A2 receptors: comparison to rat platelets

Folger, Walter; Halushka, Perry V.; Wilcox, Christopher S.; Guzmán, Nicolás

doi:10.1016/0922-4106(92)90144-k

Cited by 16 publications

(11 citation statements)

References 24 publications

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“…In adrenergic receptors, the seventh transmembrane domain has been suggested to regulate receptor-ligand binding (43,44). In this seventh transmembrane region of rTX receptor, the amino acid residues of Arg-292 and Trp-296 which are considered to be crucial for specific ligand binding (14,39) (17,18). In the present study, we also confirmed the presence of functional receptor in rat mesangial cells (Fig.…”

Section: Resultssupporting

confidence: 78%

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Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization.

et al. 1995

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Section: Resultssupporting

confidence: 78%

“…The receptor mRNA is expressed mainly in the brain, thymus, heart, liver, spleen, uterus, and in the kidney. In isolated renal glomeruli (3,17), cultured renal glomerular mesangial cells (18,19), and epithelial cells of urinary bladder (20) (14,15,28).…”

Section: Introductionmentioning

confidence: 99%

Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization.

et al. 1995

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“…Several laboratories have compared the ligand binding characteristics of human platelet and rat vascular TP and have found that the rat receptor exhibits unique pharmacology exemplified by a binding affinity for the agonist 125 I-BOP, which is 10-fold greater than human TP (3,10,11,12). A comparative study of transfected human TP␣ and rat TP has confirmed these findings (7).…”

supporting

confidence: 56%

Structural Determinants for Agonist Binding Affinity to Thromboxane/Prostaglandin Endoperoxide (TP) Receptors

Dorn

Davis

D'Angelo

1997

Journal of Biological Chemistry

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The two most extensively characterized thromboxane/ prostaglandin endoperoxide (TP) receptors, from human platelets and rat vascular smooth muscle, exhibit thromboxane agonist [15-(1␣,2␤(5Z),3␣-(1E,3S),4␣)]-7-[3-hydroxy-4-(p-iodophenoxy)-1-butenyl-7-oxabicycloheptenoic acid (I-BOP) binding affinities that differ by an order of magnitude, rat TP having the higher affinity. We utilized this difference in I-BOP affinity to identify structural determinants of TP receptor heterogeneity. No significant difference was found in the rank order of affinities for a series of thromboxane receptor ligands to bind to cloned human TP␣ versus rat TP, indicating that these represent species homologs, not distinct TP subtypes. Structural determinants for observed differences in I-BOP binding Thromboxane A 2 is one of the most potent platelet-aggregating and vasoconstricting agents known. High affinity interactions of thromboxane A 2 or prostaglandin H 2 (1, 2) and lower affinity interactions of prostaglandin F 2 ␣, and E 2 (3) at membrane thromboxane/prostaglandin endoperoxide (TP) 1 receptors transduce these effects in platelets and vascular smooth muscle. To date, two human TP subtypes as well as mouse and rat TP have been cloned (4 -8). The two human subtypes, designated TP␣ and TP␤, are the alternately spliced products of a single gene, diverge only in the intracellular carboxyl terminus, and display identical ligand binding characteristics but different patterns of coupling to G-protein effectors (9).The cloned rat and mouse TP are 93% identical at the amino acid level, while, compared with the human TP␣, the rat TP is 73% identical. Several laboratories have compared the ligand binding characteristics of human platelet and rat vascular TP and have found that the rat receptor exhibits unique pharmacology exemplified by a binding affinity for the agonist 125 I-BOP, which is 10-fold greater than human TP (3,10,11,12). A comparative study of transfected human TP␣ and rat TP has confirmed these findings (7).There is a great deal of interest in identifying the structural determinants of thromboxane receptor ligand binding due to the potential for development and refinement of subtype-specific agonists and antagonists. To date, two studies have employed mutagenesis to examine the effects of single amino acid substitutions on ligand binding. Funk et al. (13) modified several amino acids within the seventh transmembrane-spanning domain of human TP␣ and characterized changes in antagonist binding. However, since the amino acids in transmembrane domain 7 are absolutely conserved in all known TP receptors, these studies do not help to define differences between the naturally occurring receptors. In the second study, our laboratory examined the functional consequences of substitution mutagenesis of cysteine residues within human TP␣ and identified three cysteines that affected ligand binding (14). Cysteines 105 and 184, in the first and second extracellular loops, respectively, were absolutely required for binding and were assumed to f...

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“…However, the level of a-BSA in the plasma was never affected by the treatment of the TXA2 receptor antagonists or the TXA2 synthase inhibitors. In addition, we determined the level of a-BSA in the glomeruli and plasma after the injection of U-46619, a TXA2 analogue, into the a-BSA-charged mice because U-46619 was demonstrated to bind to TXA2 receptors in glomerular membrane (31). The mice treated with U-46619 showed more a-BSA in the glomeruli than the control mice, yet the plasma level of a-BSA was similar to that in the control mice, suggesting that TXA2 interferes with the clearance of aggregated protein in the glomeruli.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane A2 Interferes with a Disposal Process of Aggregated Protein in Glomeruli

Nagamatsu

Nagao

Nomura

et al. 1997

Japanese Journal of Pharmacology

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ABSTRACT-Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were un dertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumu lated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin 12 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor an tagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly in creased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective inter vention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.

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Characterization of rat glomerular thromboxane A2 receptors: comparison to rat platelets

Cited by 16 publications

References 24 publications

Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization.

Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization.

Structural Determinants for Agonist Binding Affinity to Thromboxane/Prostaglandin Endoperoxide (TP) Receptors

Thromboxane A2 Interferes with a Disposal Process of Aggregated Protein in Glomeruli

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