Featured Article: Differential regulation of endothelial nitric oxide synthase phosphorylation by protease-activated receptors in adult human endothelial cells

Tillery, Lakeisha; Epperson, Tenille; Eguchi, Satoru; Motley, Evangeline D.

doi:10.1177/1535370215622584

Cited by 11 publications

(8 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, extensive unbiased and enhanced sampling MD simulations could provide additional insight, at the atomic level, into the numerous questions about the inner structural organization of NOSred, such as: i) What are the mechanisms of NOSred activity modulation by the regulatory elements? ii) Which structural changes are induced by PTMs in this domain (including phosphorylation of several serines in cNOSs, phosphorylation of Thr 495 and S -glutathionylation of Cys 689 and Cys 908 in eNOS [ 81 , [104] , [105] , [106] ])? iii) Are the regulatory mechanisms of the NOS isoforms different?…”

Section: Nos Structurementioning

confidence: 99%

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Bignon

Rizza

Filomeni

et al. 2019

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

Nitric oxide (NO) is an essential signaling molecule in the regulation of multiple cellular processes. It is endogenously synthesized by NO synthase (NOS) as the product of L-arginine oxidation to L-citrulline, requiring NADPH, molecular oxygen, and a pterin cofactor. Two NOS isoforms are constitutively present in cells, nNOS and eNOS, and a third is inducible (iNOS). Despite their biological relevance, the details of their complex structural features and reactivity mechanisms are still unclear. In this review, we summarized the contribution of computational biochemistry to research on NOS molecular mechanisms. We described in detail its use in studying aspects of structure, dynamics and reactivity. We also focus on the numerous outstanding questions in the field that could benefit from more extensive computational investigations.

show abstract

Section: Nos Structurementioning

confidence: 99%

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Bignon

Rizza

Filomeni

et al. 2019

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

show abstract

“…It has been reported that PAR2 activation leads to vasodilation of dural arteries in rodents and this in part is mediated by modulation of NO [ 17 , 24 ]. PAR2 has also been shown to increase NO production in multiple cell types via activation of NO synthase [ 24 – 26 ]. We have previously shown that PAR2 both promotes prostaglandin E2 (PGE2) production and increases sensitivity to PGE2 associated with transition to the chronic pain state [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

PAR2 activation in the dura causes acute behavioral responses and priming to glyceryl trinitrate in a mouse migraine model

Mason

Hassler

DeFea³

et al. 2023

J Headache Pain

View full text Add to dashboard Cite

Background Migraine is a severely debilitating disorder that affects millions of people worldwide. Studies have indicated that activation of protease-activated receptor-2 (PAR2) in the dura mater causes headache responses in preclinical models. It is also well known that vasodilators such as nitric oxide (NO) donors can trigger migraine attacks in migraine patients but not controls. In the current study we examined whether activation of PAR2 in the dura causes priming to the NO donor glyceryl trinitrate (GTN). Methods A preclinical behavioral model of migraine was used where stimuli (PAR2 agonists: 2at-LIGRL-NH2 (2AT) or neutrophil elastase (NE); and IL-6) were applied to the mouse dura through an injection made at the intersection of the lamdoidal and sagittal sutures on the skull. Following dural injection, periorbital von Frey thresholds and facial grimace responses were measured until their return to baseline. GTN was then given by intraperitoneal injection and periorbital hypersensitivity and facial grimace responses observed until they returned to baseline. Results We found that application of the selective PAR2 agonist 2at-LIGRL-NH2 (2AT) onto the dura causes headache-related behavioral responses in WT but not PAR2−/− mice with no differences between sexes. Additionally, dural PAR2 activation with 2AT caused priming to GTN (1 mg/kg) at 14 days after primary dural stimulation. PAR2−/− mice showed no priming to GTN. We also tested behavioral responses to the endogenous protease neutrophil elastase, which can cleave and activate PAR2. Dural neutrophil elastase caused both acute responses and priming to GTN in WT but not PAR2−/− mice. Finally, we show that dural IL-6 causes acute responses and priming to GTN that is identical in WT and PAR2−/− mice, indicating that IL-6 does not act through PAR2 in this model. Conclusions These results indicate that PAR2 activation in the meninges can cause acute headache behavioral responses and priming to an NO donor, and support further exploration of PAR2 as a novel therapeutic target for migraine.

show abstract

“…This study showed that PAR-2 deficiency increased the phosphorylation and expression of eNOS in vivo after the injection of C48/80. PAR-2 has been reported to be expressed in endothelial Although some reports have shown that PAR-2 activation results in the phosphorylation of eNOS at Ser1177 in human endothelial cells and rat aorta with metabolic syndrome [29][30][31], another study reported that PAR-2 suppressed eNOS phosphorylation at Ser1177 in the aorta of diabetic mice [32].…”

Section: Discussionmentioning

confidence: 99%

Protective role of protease-activated receptor-2 in anaphylaxis model mice

Nakazawa

Tochinai

Fujii

et al. 2023

Preprint

View full text Add to dashboard Cite

Anaphylaxis is a severe life-threatening hypersensitivity reaction induced by mast cell degranulation. Among the various mediators of mast cells, little is known about the role of tryptase. Therefore, we aimed to elucidate the role of protease-activating receptor-2 (PAR-2), a receptor activated by tryptase, in murine anaphylactic models using PAR-2-deficient mice and newly generated tryptase-deficient mice. Anaphylaxis was induced by IgE-dependent and IgE-independent mast cell degranulation in mice. PAR-2 deficiency exacerbated the decrease in body temperature and hypotension during anaphylaxis; however, the number of skin mast cells, degree of mast cell degranulation, and systemic and local vascular hyperpermeability were comparable in PAR-2 knockout and wild-type mice. Nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), is an indispensable vasodilator in anaphylaxis. In the lungs of anaphylactic mice, PAR-2 deficiency promoted eNOS expression and phosphorylation, suggesting a protective effect of PAR-2 against anaphylaxis by downregulating eNOS activation and expression. Based on the hypothesis that the ligand for PAR-2 in anaphylaxis is mast cell tryptase, tryptase-deficient mice were generated using CRISPR-Cas9. In wild-type mice, the PAR-2 antagonist exacerbated the body temperature drop due to anaphylaxis; however, the effect of the PAR-2 antagonist was abolished in tryptase-deficient mice. These results suggest that tryptase is a possible ligand of PAR-2 in anaphylaxis and that the tryptase/PAR-2 pathway attenuates the anaphylactic response in mice.

show abstract

Featured Article: Differential regulation of endothelial nitric oxide synthase phosphorylation by protease-activated receptors in adult human endothelial cells

Cited by 11 publications

References 42 publications

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase

PAR2 activation in the dura causes acute behavioral responses and priming to glyceryl trinitrate in a mouse migraine model

Protective role of protease-activated receptor-2 in anaphylaxis model mice

Contact Info

Product

Resources

About