Bradykinin receptors in GtoPdb v.2021.3

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [91]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema

Bradykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [76]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema

Bradykinin receptors in GtoPdb v.2023.1

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023

The Human Gonadotropin Releasing Hormone Type I Receptor Is a Functional Intracellular GPCR Expressed on the Nuclear Membrane

The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor

Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites

Différenciation des sous-types du récepteur B2 de la bradykinine chez diverses espèces animales

La bradykinine, la desArg®BK et quelques analogues agonistes ainsi que plusieurs antagonistes des kinines ont été testés in vitro sur des organes isolés afin d'identifier les sous-types du récepteur B2 de la bradykinine. La caractérisation pharmacologique initiale a été effectuée sur la veine jugulaire de lapin et l'iléon de cobaye, deux préparations largement utilisées et qui montrent des différences marquées dans leurs sensibilités aux agonistes et antagonistes. L'étude a été prolongée par la suite sur des tissus périphériques (estomac, côlon et vessie) et des vaisseaux isolés (e.g. veine cave de lapin, veine porte de rat et l'artère pulmonaire de cobaye) provenant de lapin, cobaye, rat et d'homme, dans le but de déterminer si les sous-types de récepteurs pharmacologiques peuvent être liés à l'espèce. Les résultats obtenus ont montrés que les récepteurs B2 de rat et de cobaye appartiennent possiblement à la même entité pharmacologique, un récepteur qui serait différent de celui médiant la réponse sur les tissus de lapin et de l'homme. L'ordre de puissance des agonistes obtenu ([Hyp3]BK > BK > [Aib7]BK) sur la veine jugulaire de lapin est différent de celui trouvé sur l'iléon de cobaye, qui est le suivant: (BK ? [Aib7]BK > (Hyp3]BK). Les affinités des antagonistes compétitifs (comme exemple, le DArg[Hyp3,DPhe7,Leu8]BK) sur les tissus de lapin sont plus élevées, par comparaison aux tissus de cobaye et de rats, d'environ deux unités logarythmiques et plus, tandis que le composé non peptidique WIN 64338 est plus actif (lui aussi d'environ deux unités logarythmiques et plus) sur les tissus de cobayes que sur les tissus de lapin et de l'homme. L'antagoniste non compétitif à longue durée d'action, le HOE 140, est également actif et très puissant chez les quatres espèces étudiées. Les interférences métaboliques ont été largement éliminées par utilisation d'inhibiteurs de peptidases. Quelques antagonistes des trois catégories (peptides avec et sans résidus non-naturels et composé non peptidique) ont été montrés spécifiques et sélectifs des récepteurs B2 de la bradykinine. Mis ensemble, les résultats présentés a) confirment l'existence de deux sous-types du récepteur B2, b) suggèrent que les sous-types de récepteurs sont dépendants de l'espèces, c) indiquent que le sous-type du récepteur B2 retrouvé chez le lapin est semblable à celui retrouvé chez l'homme

Différenciation des sous-types du récepteur B2 de la bradykinine chez diverses espèces animales

La bradykinine, la desArg®BK et quelques analogues agonistes ainsi que plusieurs antagonistes des kinines ont été testés in vitro sur des organes isolés afin d'identifier les sous-types du récepteur B2 de la bradykinine. La caractérisation pharmacologique initiale a été effectuée sur la veine jugulaire de lapin et l'iléon de cobaye, deux préparations largement utilisées et qui montrent des différences marquées dans leurs sensibilités aux agonistes et antagonistes. L'étude a été prolongée par la suite sur des tissus périphériques (estomac, côlon et vessie) et des vaisseaux isolés (e.g. veine cave de lapin, veine porte de rat et l'artère pulmonaire de cobaye) provenant de lapin, cobaye, rat et d'homme, dans le but de déterminer si les sous-types de récepteurs pharmacologiques peuvent être liés à l'espèce. Les résultats obtenus ont montrés que les récepteurs B2 de rat et de cobaye appartiennent possiblement à la même entité pharmacologique, un récepteur qui serait différent de celui médiant la réponse sur les tissus de lapin et de l'homme. L'ordre de puissance des agonistes obtenu ([Hyp3]BK > BK > [Aib7]BK) sur la veine jugulaire de lapin est différent de celui trouvé sur l'iléon de cobaye, qui est le suivant: (BK ? [Aib7]BK > (Hyp3]BK). Les affinités des antagonistes compétitifs (comme exemple, le DArg[Hyp3,DPhe7,Leu8]BK) sur les tissus de lapin sont plus élevées, par comparaison aux tissus de cobaye et de rats, d'environ deux unités logarythmiques et plus, tandis que le composé non peptidique WIN 64338 est plus actif (lui aussi d'environ deux unités logarythmiques et plus) sur les tissus de cobayes que sur les tissus de lapin et de l'homme. L'antagoniste non compétitif à longue durée d'action, le HOE 140, est également actif et très puissant chez les quatres espèces étudiées. Les interférences métaboliques ont été largement éliminées par utilisation d'inhibiteurs de peptidases. Quelques antagonistes des trois catégories (peptides avec et sans résidus non-naturels et composé non peptidique) ont été montrés spécifiques et sélectifs des récepteurs B2 de la bradykinine. Mis ensemble, les résultats présentés a) confirment l'existence de deux sous-types du récepteur B2, b) suggèrent que les sous-types de récepteurs sont dépendants de l'espèces, c) indiquent que le sous-type du récepteur B2 retrouvé chez le lapin est semblable à celui retrouvé chez l'homme

Plateletactivating factor in vasoobliteration of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43

PURPOSE. To test whether platelet-activating factor (PAF) directly causes retinovascular endothelial cell (EC) death. METHODS. Retinovascular density was calculated in rat pups exposed to 80% O 2 from postnatal days (P)6 to P14 (to produce oxygen-induced retinopathy [OIR]), using the adenosine diphosphatase (ADPase) technique, in animals treated with distinct PAF receptor blockers (PCA-4248, BN52021, or THG315). PAF levels were then measured in the retinas. Viability of ECs from piglets and humans in response to C-PAF (a stable PAF analogue) was determined by the reduction of the tetrazolium salt 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) by viable cells, incorporation of propidium iodide (PI), TUNEL assay, and release of lactate dehydrogenase. Release of thromboxane (TX) was measured in the cell media. RESULTS. PAF levels in retina were markedly increased by exposure of isolated rat retinas to H 2 O 2 (1 M) and of rat pups placed in 80% O 2 . Exposure to 80% O 2 induced retinal vasoobliteration, which was equally significantly inhibited (ϳ60%) by all PAF receptor blockers tested. C-PAF increased incorporation of PI by isolated rat retinal microvasculature. Also, C-PAF caused time-and concentration-dependent death of cultured retinal ECs, which was prevented by the PAF receptor antagonist CV-3988. This effect of C-PAF was selective on retinal and neurovascular ECs, but not on other ECs. DNA fragmentation (TUNEL) was hardly detected, and inhibition of apoptosis-related processes by nicotinamide, cyclosporin A, and Z-DEVD-FMK and Z-VAD-FMK (caspase inhibitors) barely protected against death in EC, whereas C-PAF increased release of lactate dehydrogenase, implying that necrosis is the nature of EC death. Finally, C-PAF-induced cell death was preceded by an increase in TXB 2 levels and was prevented by TXA 2 synthase inhibition (with CGS12970). CONCLUSIONS. The data suggest PAF plays a major role in vasoobliteration in OIR by triggering death of neuroretinal microvascular ECs. The cell death seems to be mediated at least in part by TXA 2 . These effects of PAF may participate in ischemic retinopathies such as diabetes and retinopathy of prematurity. (Invest Ophthalmol Vis Sci. 2002;43:3327-3337

Effect of epitope tag on hGnRH-RI signaling and spatial localization of FLAG-hGnRH-RI.

<p>(A) Inositol phosphate (IP) production in response to 100 nM Buserelin was assessed as described in “<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0011489#s4" target="_blank">Materials and Methods</a>”. Data represent three to six independent experiments performed in triplicate and normalized to FLAG-hGnRHRI ± S.E. (B, left) HTR-8/SVneo cells transfected with either FLAG-hGnRH-RI (a) subjected to indirect immunofluorescent staining using affinity purified rabbit anti-FLAG antibody followed by Alexa Fluor 568-conjugated anti-rabbit IgG (<i>red</i>) and counterstained with the nuclear dye, Hoechst (<i>blue</i>). Note the perinuclear localization of the FLAG-tagged hGnRH-RI (<i>a</i>, <i>arrow</i>); (B, right) HTR-8/SVneo cell transfected with GnRH-RI-GFP and counterstained with the nuclear dye, Hoechst (<i>blue</i>). Note the perinuclear localization of the GnRH-RI-GFP. (C) HTR-8/SVneo and HEK 293 cells transfected with FLAG-hGnRH-RI were subjected to indirect immunofluorescent staining using affinity purified rabbit anti-FLAG antibody followed by Alexa Fluor 568-conjugated anti-rabbit IgG (<i>red</i>) and counterstained with Hoechst (<i>blue</i>). Note the perinuclear localization of the FLAG-tagged hGnRH-RI seen in both cell lines (<i>arrows</i>). Bright field images are shown in the second column from the left. (D) Western blot analysis was performed on the lysates of nuclei isolated from HEK 293 cells overexpressing FLAG-GnRH-RI. The results reveal that the full length hGnRH-RI is expressed on the nuclei of HEK 293 cells. (E) Cells expressing FLAG-hGnRH-RI were subjected to indirect immunofluorescent staining for the receptor (red) as well as the nuclear membrane, endoplasmic reticulum and Golgi (<i>all shown in green</i>). Colocalization is seen as yellow staining. Column A: receptor alone; Column B: receptor + Hoescht; Column C: organelle marker (lamin A/C, calnexin or GM130) + Hoescht; Column D: receptor + organelle marker. Column letters and roman numerals used as a coordinate system. hGnRH-RI immunoreactivity co-localized with the nuclear marker, lamin A/C, as seen by the yellow staining (I-D, II-D, <i>arrows</i>) as well as with the endoplasmic reticulum marker, calnexin (III-D, IV-D). Less colocalization was seen between the receptor and the Golgi, as shown by less yellow staining (V-D, VI-D). Scale bar = 10 µm.</p

Spatial localization of FLAG-human-<i>Xenopus</i> (HX)-GnRH-RI and FLAG-<i>Xenopus</i> (X)-GnRH-RI in HEK 293 cells using organellar markers.

<p>Cells expressing FLAG-GnRH-RI (HX and X) were subjected to indirect immunofluorescent staining for the receptor (red) as well as the nuclear membrane, endoplasmic reticulum and Golgi (<i>all shown in green</i>). Colocalization is seen as yellow staining. Column A: receptor alone; Column B: receptor + Hoescht; Column C: organelle marker (lamin A/C, calnexin or GM130) + receptor; Column D: receptor + organelle marker. Column letters and roman numerals used as a coordinate system. HX-GnRH-RI immunoreactivity co-localized with the nuclear marker, lamin A/C, as seen by the yellow staining (I-D, <i>arrow</i>) as well as the endoplasmic reticulum marker, calnexin (II-D). Less colocalization was seen between the receptor and the Golgi, as shown by less yellow staining (III-D). X-GnRH-RI immunoreactivity strongly localized to the plasma membrane (yellow arrowheads) and weakly in cytoplasm. No visual co-localization detected with lamin A/C (IV-D, <i>arrow</i>), calnexin (V-D) or Golgi (VI-D). Scale bar = 10 µm.</p