Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

Thomas, Dennis W.; Mannon, Roslyn B.; Mannon, Peter J.; Latour, Anne M.; Oliver, Julie A.; Hoffman, Maureane; Smithies, Oliver; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1172/jci5116

Cited by 243 publications

(167 citation statements)

References 47 publications

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“…While EP 1 , FP and TP receptors are each broadly classified as members of the contractile subgroup of prostanoid receptors , functionally they are primarily associated with distinct physiologic processes and each exhibit distinct patterns of expression Sugimoto et al, 2000). Consistent with the latter, mice deficient in each of these receptors display unique characteristic phenotypes including a reduction in carcinogen-induced colorectal cancer in EP 1 -deficient mice (Ushikubi et al, 1998;Watanabe et al, 1999;Sugimoto et al, 2000), loss of parturition affecting both ovulation and fertilization in FPdeficient mice Hizaki et al, 1999;Kennedy et al, 1999) and increased bleeding tendency associated with TP-deficient mice (Thomas et al, 1998). While EP 1 , FP and TP receptors are also abundantly expressed in the kidney (Sugimoto et al, 2000) and they are each reported to mediate efficient contraction of renal vascular SM and mesangial cells through Ca 2 þ -dependent mechanisms (Mene et al, 1989), their role in renal function as garnered from mouse knockout studies remains to be clearly established.…”

Section: Discussionmentioning

confidence: 89%

EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor

Kelley-Hickie

Kinsella

2004

British J Pharmacology

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1 Heterologous desensitization or intermolecular cross-talk plays a critical role in regulating intracellular signalling by diverse members of the G-protein-coupled receptor superfamily. We have previously established that the a and b isoforms of the human thromboxane A 2 receptor (TP) undergo differential desensitization of signalling in response to 17 phenyl trinor prostaglandin (PG)E 2 , an agonist of the EP 1 subtype of the PGE 2 receptor (EP) family. 2 Herein, we investigated the molecular basis of TPa and TPb desensitization in human embryonic kidney (HEK) 293 cells and in renal mesangial cells in response to 17 phenyl trinor PGE 2 and in response to the PGF 2a receptor (FP) agonist PGF 2a , and sought to identify the target site(s) of those desensitizations.3 Our results demonstrated that TPa and TPb receptors are subject to desensitization in response to both EP 1 and FP receptor activation and that these effects are mediated by direct protein kinase (PK)C phosphorylation of the individual TP isoforms within their unique carboxyl-terminal (C)-tail domains. 4 Moreover, deletion/site-directed mutagenesis and metabolic labelling studies identified Thr 337 , within TPa, and Thr 399 , within TPb, as the specific target residues for PKC phosphorylation and EP 1 -and FP-mediated desensitization of TPa and TPb signalling, respectively. 5 Hence, in conclusion, while the TPa and TPb diverge within their C-tail domains, they have evolved to share a similar mechanism of PKC-induced phosphorylation and desensitization in response to EP 1 and FP receptor activation, though it occurs at sites unique to the individual TP isoforms.

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Section: Discussionmentioning

confidence: 89%

EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor

Kelley-Hickie

Kinsella

2004

British J Pharmacology

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“…The TP receptor is involved in platelet aggregation and prolonged receptor antagonism extends bleeding times in animals. 42,43 Moreover, humans with a gene defect in the TP receptor have an increased risk of bleeding. 44,45 Thus, we believe it is desirable to identify BBBpermeable TP receptor antagonists to minimize possible negative effects on hemostasis for indications where prolonged dosing would be required, such as AD.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Soper

Sugiyama

Herbst-Robinson

et al. 2012

ACS Chem. Neurosci.

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A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. KEYWORDS: Alzheimer's disease, amyloid precursor protein, antagonist, blood-brain barrier, plaques, thromboxane receptor A lzheimer's disease (AD) is the most common cause of dementia in elderly populations, affecting approximately 10% of individuals over age 65. 1,2 The AD brain is characterized by overt neurodegeneration 3 and the presence of senile plaques comprising insoluble fibrils of Aβ peptides which are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP). 4 A second pathological hallmark of the AD brain is the occurrence of intracellular inclusions composed of hyperphosphorylated tau proteins. 5,6 Familial forms of AD can be caused by mutations in APP that result in increased proteolytic generation of amyloidogenic Aβ peptides, as well as by mutations in the presenilin proteins that are required for the proteolytic processing of APP to yield Aβ. 7−10 These genetic data provide compelling support for the "amyloid" hypothesis, which postulates that it is the production of Aβ that drives disease pathogenesis in AD. Accordingly, there is significant interest in identifying therapeutic strategies that will lead to decreased Aβ production, and there are ongoing efforts to identify inhibitors of the enzymes that generate Aβ. 11,12 A consequence of Aβ plaque deposition in the AD ...

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“…Tx is involved in blood platelet function and linked with hemostasis and thrombosis [12,13]. The TP receptors density has been reported to be enhanced in cardiovascular disease [14] and in hypertension [15].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

Zhang

Edvinsson

et al. 2008

Atherosclerosis

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Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

Cited by 243 publications

References 47 publications

EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor

EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

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Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

Cited by 243 publications

References 47 publications

EP1‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A2 receptor

EP1‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A2 receptor

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

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EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor

EP₁‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A₂ receptor