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- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Journal of High Energy Physics. - : Springer-Verlag New York. - 1029-8479 .- 1126-6708. ; :9
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Tidskriftsartikel (refereegranskat)
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- Holm, Anders, et al.
(författare)
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The G protein-coupled oestrogen receptor 1 agonist G-1 disrupts endothelial cell microtubule structure in a receptor-independent manner.
- 2012
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Ingår i: Molecular and Cellular Biochemistry. - : Springer Science and Business Media LLC. - 0300-8177 .- 1573-4919. ; 366:1-2, s. 239-249
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Tidskriftsartikel (refereegranskat)abstract
- The G protein-coupled oestrogen receptor GPER1, also known as GPR30, has been implicated in oestrogen signalling, but the physiological importance of GPER1 is not fully understood. The GPER1 agonist G-1 has become an important tool to assess GPER1-mediated cellular effects. Here, we report that this substance, besides acting via GPER1, affects the microtubule network in endothelial cells. Treatment with G-1 (3 μM) for 24 h reduced DNA synthesis by about 60 % in mouse microvascular endothelial bEnd.3 cells. Treatment with 3 μM G-1 prevented outgrowth of primary endothelial cells from mouse aortic explants embedded in Matrigel. Treatment with G-1 (0.3-3 μM) for 24 h disrupted bEnd.3 cell and HUVEC microtubule structure in a concentration-dependent manner as assessed by laser-scanning confocal immunofluorescence microscopy. G-1-induced (3 μM) disruption of microtubule was observed also after acute (3 and 6 h) treatment and in the presence of the protein synthesis inhibitor cycloheximide. Disruption of microtubules by 3 μM G-1 was observed in aortic smooth muscle cells obtained from both GPER1 knockout and wild-type mice, suggesting that G-1 influences microtubules through a mechanism independent of GPER1. G-1 dose dependently (10-50 μM) stimulated microtubule assembly in vitro. On the other hand, microtubules appeared normal in the presence of 10-50 μM G-1 as determined by electron microscopy. We suggest that G-1-promoted endothelial cell anti-proliferation is due in part to alteration of microtubule organization through a mechanism independent of GPER1. This G-1-promoted mechanism may be used to block unwanted endothelial cell proliferation and angiogenesis such as that observed in, e.g. cancer.
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- Maurer, M, et al.
(författare)
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New topics in bradykinin research
- 2011
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 66:11, s. 1397-1406
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Tidskriftsartikel (refereegranskat)abstract
- Bradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B(1) and B(2) receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.
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- Olde, Bjorn, et al.
(författare)
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G protein-coupled Receptor 30 (GPR30) PDZ-dependently and Constitutively Increases ERK1/2 Signaling Through Calcineurin and Kinase Suppressor of Ras 2 (KSR2)
- 2016
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Ingår i: FASEB Journal. - 0892-6638. ; 30:1 Suppl, s. 518-518
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Konferensbidrag (refereegranskat)abstract
- The objective of the present study was to map the mechanism whereby G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor (GPER), stimulates extracellular signal-regulated kinase (ERK)1/2 signaling. GPR30 plays important roles in cancer and cardiometabolic regulation. We showed recently that GPR30 forms a plasma membrane complex through its C-terminal type I PSD-95/Discs-large/ZO-1 homology (PDZ) motif with a membrane-associated guanylate kinase (MAGUK) and protein kinase A (PKA)-anchoring protein 5 (AKAP5), and AKAP5-anchored PKA regulatory subunit RII suppresses receptor endocytosis and enables the receptor to constitutively inhibit cAMP production. Here, we investigated if this PDZ-dependent GPR30 complex also regulates ERK1/2 signaling. To do so, human and mouse GPR30 were ectopically expressed in HEK293 cells and MDCK cells, and receptors and effectors were monitored by immunoblotting, immunoprecipitation, confocal immunofluorescence microscopy, split luciferase reporter techniques, and reporter gene assays. We found that GPR30 constitutively increased extracellular signal-regulated kinase (ERK) 1/2 activity in several cell systems. The response was dependent on an intact receptor PDZ motif. Furthermore, knocking down AKAP5 or inhibiting calcineurin with FK506 inhibited the receptor response. GPR30 PDZ-dependently inhibited basal NFAT signaling, consistent with the receptor favoring AKAP5-anchoring of calcineurin. The calcineurin substrate kinase suppressor of Ras 2 (KSR2), a mitogen-activated protein kinase (MAPK) scaffold, enhanced the GPR30-promoted response, also dependently on the receptor PDZ motif. GPR30 also PDZ-dependently favored a membrane KSR2 complex at the expense of the monomeric form. On the other hand, disrupting AKAP5-PKA RII interaction with St-Ht31, or inhibiting protein kinase C (PKC) with GF109203X or epidermal growth factor receptor (EGFR) tyrosine kinase with AG1478 had no effect on the GPR30-stimulated response. FK506 also increased the amount of GPR30 in the plasma membrane, thus acting opposite to St-Ht31, which increased receptor endocytosis. We conclude that the PDZ-dependent GPR30 complex with AKAP5 includes calcineurin, which favors GPR30 endocytosis and enables the receptor to constitutively increase ERK1/2 signaling through KSR2. Support or Funding Information Swedish Cancer Foundation
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