scholarly journals Bradykinin B2 receptor and dopamine D2 receptor cooperatively contribute to the regulation of neutrophil adhesion to endothelial cells*

2018 ◽  
Vol 65 (3) ◽  
pp. 367-375 ◽  
Author(s):  
Anna Niewiarowska-Sendo ◽  
Anna Łabędź-Masłowska ◽  
Andrzej Kozik ◽  
Ibeth Guevara-Lora
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Dopamine D2 Receptor ◽  
Leukocyte Adhesion ◽  
D2 Receptor ◽  
Protective Role ◽  
Receptor Type ◽  
Cellular Functions ◽  
Stat3 Phosphorylation

Leukocyte adhesion to the vascular endothelium contributes to many immunological and inflammatory disorders. These processes have been shown to be mediated by bradykinin receptor type 2 (B2R) and dopamine receptor type 2 (D2R). In a previous study, we reported the formation of a B2R-D2R heterodimer, possibly altering cellular functions. Hence, in the present study, we examined the effect of co-activation of endothelial cells with B2R and D2R agonists on the interaction of these cells with neutrophils. Bradykinin, the main B2R agonist, significantly increased cell adhesion, and this effect was reversed when the endothelial cells were additionally co-treated with a selective D2R agonist, sumanirole. These results were dependent on the incubation time, showing an opposite tendency after prolonged stimulation. Significant changes in the expression of adhesion proteins, such as E-selectin and intracellular adhesion molecule 1 in endothelial cells were observed. Additionally, the cells preincubated with tumor necrosis factor-a showed decreased cell adhesion and IL-8 release after long incubation with both agonists. The modulation of cell adhesion by D2R and B2R seem to be mediated via STAT3 phosphorylation. In summary, this study demonstrated a protective role of D2R in neutrophil-endothelial cell adhesion induced by bradykinin, especially in cytokine-stimulated endothelial cells.

scholarly journals Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways

2018 ◽  
Vol 115 (27) ◽  
pp. 7051-7056 ◽  
Author(s):  
M. Young ◽  
T. Dahoun ◽  
B. Sokrat ◽  
C. Arber ◽  
K. M. Chen ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
High Specificity ◽  
Computational Design ◽  
Membrane Receptor ◽  
Membrane Receptors ◽  
Cellular Functions ◽  
Hierarchical Code

Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein–coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways. Using this approach, we designed orthogonal D2–Gi complexes, which coupled with high specificity and triggered exclusively the Gi-dependent signaling pathway. We also engineered an orthogonal chimeric D2–Gs/i complex that rewired D2 signaling from a Gi-mediated inhibitory into a Gs-dependent activating pathway. Reinterpreting the evolutionary history of GPCRs in light of the designed proteins, we uncovered an unforeseen hierarchical code of GPCR–G-protein coupling selectivity determinants. The results demonstrate that membrane receptor–cytosolic protein systems can be rationally engineered to regulate mammalian cellular functions. The method should prove useful for creating orthogonal molecular switches that redirect signals at the cell surface for cell-engineering applications.

scholarly journals Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

2020 ◽  
Vol 21 (11) ◽  
pp. 3809 ◽  
Author(s):  
Francesca Rossi ◽  
Chiara Tortora ◽  
Maura Argenziano ◽  
Alessandra Di Paola ◽  
Francesca Punzo
Keyword(s):  
Cannabinoid Receptor ◽  
Protective Role ◽  
Receptor Type ◽  
Macrophage Phenotype ◽  
Small Vessels ◽  
Global Pandemic ◽  
Cannabinoid Receptor Type 2 ◽  
Novel Coronavirus

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.

scholarly journals Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Erin D. Roe ◽  
Bindu Chamarthi ◽  
Philip Raskin
Keyword(s):  
Type 2 Diabetes ◽  
Pilot Study ◽  
Glycemic Control ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Insulin Requirement ◽  
High Dose ◽  
Open Label ◽  
Release Formulation

Background. The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR.Methods. Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6–4.8 mg/day) for 24 weeks. Subjects with at least one postbaselineHbA1cmeasurement (N=8) were analyzed for change from baselineHbA1c, TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT).Results. Compared to the baseline, averageHbA1cdecreased 1.76% (9.74±0.56to7.98±0.36,P=0.01), average TDID decreased 27% (199±33to147±31,P=0.009), and MMTT AUC60–240decreased 32% (P=0.04) over the treatment period. The decline inHbA1cand TDID was observed at 8 weeks and sustained over the remaining 16-week study duration.Conclusion. In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy.

scholarly journals Effects of TNF-α on Leukocyte Adhesion Molecule Expressions in Cultured Human Lymphatic Endothelium

2007 ◽  
Vol 55 (7) ◽  
pp. 721-733 ◽  
Author(s):  
Yoshihiko Sawa ◽  
Yukitaka Sugimoto ◽  
Takeshi Ueki ◽  
Hiroyuki Ishikawa ◽  
Atuko Sato ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Dependent Manner ◽  
Lymphatic Endothelium ◽  
Leukocyte Adhesion Molecule ◽  
Tnf Α ◽  
Cell Adhesion Molecule 1

TNF-α alters leukocyte adhesion molecule expression of cultured endothelial cells like human umbilical vein endothelial cells (HUVEC). This study was designed to investigate the changes in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression with TNF-α stimulation in cultured human neonatal dermal lymphatic endothelial cells (HNDLEC). The real-time quantitative PCR analysis on HNDLEC showed that TNF-α treatment leads to increases of VCAM-1 and ICAM-1 mRNAs to the 10.8- and 48.2-fold levels of untreated cells and leads to a reduction of PECAM-1 mRNA to the 0.42-fold level of untreated cells. Western blot and immunohistochemical analysis showed that TNF-α leads to VCAM-1 and ICAM-1 expressions that were inhibited by antiserum to human TNF receptor or by AP-1 inhibitor nobiletin. In flow cytometry analysis, the number of VCAM-1- and ICAM-1-positive cells increased, and PECAM-1-positive cells decreased with TNF-α treatment. Regarding protein amounts produced in cells and amounts expressed on the cell surface, VCAM-1 and ICAM-1 increased in HNDLEC and HUVEC, and PECAM-1 decreased in HNDLEC in a TNF-α concentration-dependent manner. VCAM-1, ICAM-1, and PECAM-1 protein amounts in TNF-α-stimulated cells were lower in HNDLEC than in HUVEC. This suggests that the lymphatic endothelium has the TNF-α-induced signaling pathway, resulting in increased VCAM-1 and ICAM-1 expression to a weaker extent than blood endothelium and PECAM-1 reduction to a stronger extent than blood endothelium.

scholarly journals Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy

Diabetes ◽  
2011 ◽  
Vol 60 (9) ◽  
pp. 2386-2396 ◽  
Author(s):  
F. Barutta ◽  
F. Piscitelli ◽  
S. Pinach ◽  
G. Bruno ◽  
R. Gambino ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Cannabinoid Receptor ◽  
Protective Role ◽  
Receptor Type ◽  
Cannabinoid Receptor Type 2

Pharmacology of AM211, a Potent and Selective Prostaglandin D2 Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

2011 ◽  
Vol 338 (1) ◽  
pp. 290-301 ◽  
Author(s):  
Gretchen Bain ◽  
Daniel S. Lorrain ◽  
Karin J. Stebbins ◽  
Alex R. Broadhead ◽  
Angelina M. Santini ◽  
...  
Keyword(s):  
Animal Models ◽  
D2 Receptor ◽  
Allergic Inflammation ◽  
Receptor Type ◽  
Prostaglandin D2
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