Thromboxane A2 (TP) receptor in the non-pregnant porcine myometrium and its role in regulation of spontaneous contractile activity

Cao, Jinshan; Wakatsuki, Akira; Yoshida, Munenori; Kitazawa, Takio; Taneike, Tetsuro

doi:10.1016/j.ejphar.2003.11.073

Cited by 11 publications

(9 citation statements)

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“…(2002) inferred the presence of a FP system in the non‐pregnant pig uterus on the basis of the moderately potent contractile activity of the PGF 2α analogue cloprostenol (EC 50 ∼15 nM). However, the pig uterus preparation contains both EP 3 (Okada et al ., 2000) and TP (Cao et al ., 2004) contractile systems and, as we have shown on guinea‐pig aorta (Figure 3B), cloprostenol [(+)‐isomer] can achieve considerable contractile activity through EP 3 /TP self‐synergism. The judicious use of selective prostanoid receptor antagonists ought to clarify these situations.…”

Section: Discussionmentioning

confidence: 99%

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Jones

Woodward

2010

British J Pharmacology

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BACKGROUND AND PURPOSESurprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E2 (DX-DM PGE2) on pig cerebral artery when used as a selective EP3 receptor agonist. This study investigated the selectivity profile of DX-DM PGE2, focusing on the interaction between its EP3 and TP (thromboxane A2-like) agonist activities. EXPERIMENTAL APPROACHContraction of guinea-pig trachea (EP1 system) and aorta (EP3 and TP systems) was measured in conventional organ baths. KEY RESULTSStrong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE2 (EP3 agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE2 induced strong contraction, which on the basis of treatment with (DG)-3ap (EP3 antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP3 and TP receptors. EP3/TP self-synergism also accounted for contraction induced by PGF2a and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE2 also showed significant EP1 agonism on guinea-pig trachea as defined by the EP1 antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations Ն3 mM. CONCLUSIONS AND IMPLICATIONSEP3/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP3 agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP3 system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed. AbbreviationsFA, free acid form of a C1-ester or C1-amide prostanoid; nH, Hill slope for a sigmoidal log concentration-response curve; pA2, negative logarithm of the molar concentration of antagonist producing a dose ratio of 2; pEC50, negative logarithm of the agonist concentration inducing 50% maximum response; PGE2, prostaglandin E2; pIC50, negative logarithm of the molar concentration producing 50% inhibition of an established response; TXA2, thromboxane A2 IntroductionProstaglandin E2 (PGE2) has a broad range of actions including excitation of smooth muscle cells mediated by prostanoid EP1 and EP3 receptors and inhibition mediated by EP2 and EP4 subtypes (see Coleman et al., 1994; receptor nomenclature follows Alexander et al., 2009). Its contractile action on pig BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) isolated cerebral artery has been linked to activation of both EP1 and EP3 receptors operating through the phosphatidyl inositol pathway (Jadhav et al., 2004). We had two major concerns about this study. First, very high concentrations (30-300 mM) of the EP1 antagonist AH-6809 (Coleman et al., 1985;1987) were used to identify the EP1 component and also to gauge the selectivity of 11-deoxy-16,16-dimethyl PGE2 (DX-DM PGE...

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Section: Discussionmentioning

confidence: 99%

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Jones

Woodward

2010

British J Pharmacology

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“…with that of K i values for displacement of [ 3 H]SQ29548 in several types of cells (Fukunaga et al, 1993a,b;Dorn et al, 1997;Cao et al, 2004;Wilson et al, 2004). There is no evidence, therefore, of selectivity among ligands in G␣ 13 activation apart from what can be inferred through competitive binding.…”

Section: Discussionmentioning

confidence: 99%

The G₁₂Family of G Proteins as a Reporter of Thromboxane A₂Receptor Activity

Zhang

DiLizio²,

Kim³

et al. 2006

Mol Pharmacol

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Despite advances in the understanding of pathways regulated by the G 12 family of heterotrimeric G proteins, much regarding the engagement of this family by receptors remains unclear. We explore here, using the thromboxane A 2 receptor TP␣, the ability of G 12 and G 13 to report differences in the potency and efficacy of receptor ligands. We were interested especially in the potential of the isoprostane 8-iso-prostaglandin F 2␣ (8-iso-PGF 2␣ ), among other ligands examined, to activate G 12 and G 13 through TP␣ explicitly. We were also interested in the functionality of TP␣-G␣ fusion proteins germane to G 12 and G 13 . Using fusion proteins in Spodoptera frugiperda (Sf9) cells and independently expressed proteins in human embryonic kidney 293 cells, and using guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to evaluate G␣ activation directly, we found for G␣ 13 that no ligand tested, including 8-iso-prostaglandin F 2␣ (8-iso-PGF 2␣ ) and a purported antagonist (pinane thromboxane A 2 ), was silent. The activity of agonists was especially pronounced when evaluated for TP␣-G␣ 13 and in the context of receptor reserve. Agonist activity for 8-iso-PGF 2␣ was diminished and that for pinane thromboxane A 2 nonexistent when G␣ 12 was the reporter. These data establish that G 12 and G 13 can report differentially potency and efficacy and underscore the relevance of receptor and G protein context.The G 12 family of heterotrimeric G proteins, comprising G 12 and G 13 in vertebrates, has received considerable attention for its roles in cell contractility, motility, and proliferation (for review, see Riobo and Manning, 2005). Specific functions for this family have been deduced through the actions of constitutively active G␣ subunits, effects of deleting one or both G␣ genes, effects of dominant-negative molecules, and interactions of the G␣ subunits with other proteins. Despite advances in understanding the pathways regulated by the G 12 family, however, much regarding the engagement of this family by agonists remains unclear. At a basic level, the extent to which G 12 and G 13 can report differences among agonists, for example, in terms of potency and efficacy, is entirely unknown, nor can it be easily predicted given the unusual properties of the respective G␣ subunits (Singer et al., 1994;Kozasa and Gilman, 1995). One of the problems in evaluating the dynamics of signaling through G 12 and G 13 is that enzymes or ion channels uniquely regulated by the two proteins and whose activities are easily measured have not yet been identified. A related problem is that receptors having the capacity to couple to G 12 and/or G 13 invariably couple to other G proteins as well. The analysis of proximal signaling so important to the modeling of receptor function in the context of other G proteins, therefore, has proven difficult for the G 12 family and, except for measurements of frank activation, has not been approached.Thromboxane A 2 is a member of the prostaglandin family of lipid mediators generated after cyclooxygenase-c...

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“…Both prostaglandins act on specific G proteincoupled receptors, thromboxane prostanoid receptors of TxA 2 and E prostanoid (EP-1) receptors of PGE 2 (5,19,32,33). These prostaglandin receptors couple to Gq/11 proteins causing a sustained contraction by acting on PKC (4).…”

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confidence: 98%

Reactive oxygen species are messengers in maintenance of human and guinea pig gallbladder tonic contraction

Cong

Xiao²,

Biancani³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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The tonic contraction of human and guinea pig gallbladder (GB) is dependent on basal levels of PGE(2) and thromboxane A(2) (TxA(2)). The pathway involved in the genesis of these prostaglandins has not been elucidated. We aimed to examine the source of reactive oxygen species (ROS) and whether they contribute to the genesis of GB tonic contraction by generating basal prostaglandin levels. Tonic contraction was studied in human and guinea pig GB muscle strips treated with ROS scavengers (Tiron and catalase), apocynin (an inhibitor of NADPH oxidase), and NOX-1 small interference RNA (siRNA). The subunits of NADPH oxidase and their functional roles were determined with specific antibodies in GB muscle cells. ROS scavengers reduced the GB tonic contraction and H(2)O(2) and PGE(2) levels. Apocynin also inhibited the tonic contraction. Antibodies against subunits of NADPH oxidase present in GB muscle cells lowered H(2)O(2) and PGE(2) levels. NOX-1 siRNA transfection reduced the tonic contraction, NOX-1 expression, and levels of H(2)O(2) and PGE(2). Tiron and apocynin inhibited the expected increase in tension and H(2)O(2) levels induced by stretching of muscle strips. H(2)O(2) increased the levels of PGE(2) and TxA(2) by increasing platelet-activating factor-like lipids that phosphorylate p38 and cPLA(2) sequentially. H(2)O(2) generated by NADPH oxidase participates in a signal transduction pathway that maintains the GB tonic contraction by activating PAF, p38, and cPLA(2) to generate prostaglandins.

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Thromboxane A2 (TP) receptor in the non-pregnant porcine myometrium and its role in regulation of spontaneous contractile activity

Cited by 11 publications

References 39 publications

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

The G₁₂Family of G Proteins as a Reporter of Thromboxane A₂Receptor Activity

Reactive oxygen species are messengers in maintenance of human and guinea pig gallbladder tonic contraction

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Thromboxane A2 (TP) receptor in the non-pregnant porcine myometrium and its role in regulation of spontaneous contractile activity

Cited by 11 publications

References 39 publications

Interaction of prostanoid EP3 and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE2

Interaction of prostanoid EP3 and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE2

The G12Family of G Proteins as a Reporter of Thromboxane A2Receptor Activity

Reactive oxygen species are messengers in maintenance of human and guinea pig gallbladder tonic contraction

Contact Info

Product

Resources

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Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

Interaction of prostanoid EP₃ and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE₂

The G₁₂Family of G Proteins as a Reporter of Thromboxane A₂Receptor Activity