Disease relevance of Dpt-prostaglandin E1

• In the differentiated cells, M&B28767, an EP3 agonist, caused neurite retraction in a pertussis toxin-insensitive manner [1].
• The microinjection of M&B28767 at 0.5 fg into the other parts of preoptic hypothalamus (the lateral part of the preoptic area and the median preoptic nucleus) and the diagonal band of Broca (DBB) produced hyperalgesia similar to the intraMPO-induced hyperalgesia in terms of magnitude and time course [2].
• 4. Thus, M&B 28767 and GR 63799X reduce myocardial infarct size in the rat by a mechanism(s) which involves the activation of PKC and the opening of ATP-sensitive potassium channels [3].
• In another test, M&B 28,767 (0.5-5.0 mg/kg) and DMPG (10-40 micrograms/kg) overcame morphine-induced constipation in a dose-related manner, the respective ED50s being 0.9-1.4 mg/kg and 20-40 micrograms/kg [4].

High impact information on Dpt-prostaglandin E1

• Mucin secretion and [cAMP](i) production by LS174T cells were stimulated dose-dependently by PGE(2), the EP(4)-receptor agonist 1-OH-PGE(1), and the EP(3)/EP(4) agonist M&B28767 and were inhibited with the adenylate cyclase inhibitor SQ22536 [5].
• The cytosolic level and secretion of MMP-9 were increased maximally after 24 h of incubation of HSB.2 cells with 10(-8)-10(-6) M PGE2, sulprostone, M&B 28767, and misoprostol but not with 10(-6) M PGF2alpha, PGD2, PGI2, or butaprost, suggesting a principal dependence on EP3 Rs [6].
• In the PT- and CT-treated cell membrane reconstituted with various G proteins, M&B 28767 inhibited the GTPase activity of G(o), but stimulated that of Gs [7].
• The EP3-selective agonists, M&B 28,767 or GR 63799X, potently competed for the [3H]PGE2 binding, but no competition was found with EP1- or EP2-selective ligands [8].
• PGE2 and M&B 28,767 decreased forskolin-induced cAMP formation in a concentration-dependent manner in Chinese hamster ovary cells permanently expressing the cDNA [8].

Biological context of Dpt-prostaglandin E1

• The EP3-R agonist M&B28767 induced a time- and dose-dependent phosphorylation of the FLAG-rEP3hEP4-Ct-R but not of the FLAG-rEP3beta-R [9].
• Transfection experiments revealed that all the four isoforms show high binding affinities to PGE2, PGE1, and M&B28767, an EP3-specific agonist, whereas their downstream signaling pathways are divergent [10].
• To elucidate the possible mechanism of this desensitization, in vivo phosphorylation stimulated by activators of second messenger kinases, by prostaglandin E(2), or by the EP3-R agonist M&B28767 was investigated in COS-7 cells expressing FLAG-epitope-tagged rat EP3beta-R (rEP3beta-R), hEP4-R, or rEP3hEP4-Ct-R [9].
• Both compounds given orally increased gastrointestinal motility in mice; M&B 28,767 (1-3 mg/kg) and DMPG (0.1-0.3 mg/kg) caused diarrhoea, the former being about 0.1 times as potent as the latter [4].
• The remaining four analogs, 11-deoxy PGE2-1-alcohol, MB 28767, sulprostone, and GR 63779X did not induce vasodilatation and did not potentiate FMLP exudation [11].

Anatomical context of Dpt-prostaglandin E1

• Overexpression of GRKs in FLAG-rEP3hEP4-Ct-R-expressing COS-7 cells augmented the M&B28767-induced receptor phosphorylation and receptor sequestration [9].
• Microinjection of M&B28767 (0.5 fg) into either the paraventricular nucleus, the ventromedial hypothalamus, the lateral hypothalamic area or the septal nucleus had no effect on nociception [2].
• In stably transfected CHO cells M&B 28767 > sulprostone = PGE2 > misoprostol > PGF2 alpha inhibited the forskolin-elicited cAMP formation [12].

Associations of Dpt-prostaglandin E1 with other chemical compounds

• The presence of the EP3 and EP4 Rs and the absence of the EP1 and EP2 Rs were revealed by inhibition of [3H]PGE2 binding by the EP3/EP1R agonist sulprostone, the EP3/EP2/EP4R agonist M&B 28767, and the EP2/EP4/EP3R agonist misoprostol but not by the EP1R antagonist SC-19220 or the EP2R agonist butaprost [13].
• Thus, MB 28767, sulprostone and PGE2 were potent inhibitors, whereas PGF2 alpha, PGD2 and other analogs were substantially less potent [14].
• The M&B 28767-stimulated GTPase activity consisted of pertussis-toxin-sensitive and cholera-toxin-sensitive portions in the EP3 gamma-expressing cell membrane, suggested that EP3 gamma is coupled to both guanine nucleotide-binding inhibitory and stimulatory proteins [15].

Gene context of Dpt-prostaglandin E1

• M&B28767 increased cAMP concentrations in cells expressing EP3-II and EP3-IV, whereas it inhibited forskolin-induced cAMP accumulations in cells expressing all EP3 isoforms [10].
• Signaling experiments revealed that M&B28767, an EP3 agonist, not only inhibited forskolin-induced cAMP concentrations, but also activated mitogen-activated protein kinase in Chinese hamster ovary cells stably expressing EP3-V and EP3-VI [16].
• 1. This study investigates the effects of two agonists of the prostanoid EP3-receptor (M&B 28767 and GR 63799X) on the infarct size caused by regional myocardial ischaemia and reperfusion in the anaesthetized rat [3].

References