scholarly journals Xiaoxuming Decoction Regulates Vascular Function by Modulating G Protein-Coupled Receptors: A Molecular Docking Study

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Yanjia Shen ◽  
Ran Yang ◽  
Rui Zhou ◽  
Wendan Lu ◽  
Li Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
G Protein ◽  
Vascular Tone ◽  
G Protein Coupled Receptors ◽  
Regulatory Function ◽  
Network Pharmacology ◽  
Dependent Manner ◽  
Ang Ii ◽  
Urotensin Ii ◽  
G Protein Coupled

Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.

scholarly journals Candesartan abrogates G protein-coupled receptors agonist-induced MAPK activation and cardiac myocyte hypertrophy

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S154-S161 ◽  
Author(s):  
Djamel Lebeche ◽  
Zhao Bin Kang ◽  
Roger Hajjar
Keyword(s):  
Cardiac Hypertrophy ◽  
G Protein ◽  
Map Kinases ◽  
At1 Receptor ◽  
G Protein Coupled Receptors ◽  
Neonatal Rat ◽  
Leucine Incorporation ◽  
Dependent Manner ◽  
Ang Ii ◽  
G Protein Coupled

The renin-angiotensin-aldosterone system (RAAS) has been identified as a major contributor to the development of cardiac hypertrophy and the subsequent transition to heart failure. G protein-coupled receptors agonists such as angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine (PE) have been implicated in hypertrophic responses in ventricular myocytes through the activation of several families of MAP kinases. In this study we examined the effect of candesartan, an Ang II type 1-(AT1)-receptor antagonist, on cardiac hypertrophy by using cultured neonatal rat cardiomyocytes. Stimulation with Ang II (100 nM), ET-1 (100 nM) or PE (1 µM) induced marked increases in [3H]Leucine incorporation (≥ 50%), compatible with enhanced protein synthesis. The addition of candesartan abrogated the increase in [3H]Leucine incorporation in response not only to Ang II but also to ET-1 and PE. To elucidate the mechanisms involved in this antihypertrophic effect of candesartan, we studied the activation of p38-MAPK, extracellular signal-regulated kinases (ERK1/2) and stress-activated protein kinases (SAPKs). Ang II, ET-1 and PE increased the phosphorylation levels of ERK1/2, p54 SAPK and p46SAPK and p38 in a time-dependent manner. This activation was completely blocked in the case of Ang II by pretreatment with candesartan. ET-1-induced activation of ERKs, SAPKs and p38 was also partially, but significantly, reduced by candesartan. PE-induced activation of SAPKs, but not ERKs and p38, was also reduced by candesartan. These results suggest that the hypertrophic response to ET-1 and PE, along with Ang II, is dependent upon a functioning AT1-receptor and may be mediated by AT 1 activation of the MAP kinases.

scholarly journals Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You?

2021 ◽  
Vol 73 (4) ◽  
pp. 527-565
Author(s):  
Flavio Ballante ◽  
Albert J Kooistra ◽  
Stefanie Kampen ◽  
Chris de Graaf ◽  
Jens Carlsson
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

Arrestin-2 Regulates Akt Activation by G Protein-Coupled Receptors in Platelets.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1525-1525
Author(s):  
Dongjun Li ◽  
Donna S. Woulfe
Keyword(s):  
G Protein ◽  
Genetic Manipulation ◽  
Embryonic Stem ◽  
Phosphatidyl Inositol ◽  
G Protein Coupled Receptors ◽  
Resting Cells ◽  
Dependent Manner ◽  
Akt Phosphorylation ◽  
Receptor Sites ◽  
G Protein Coupled

Abstract Arrestins have been shown to play important roles in G Protein-Coupled Receptor (GPCR) function in many cells, but their roles in platelets remain uncharacterized. While the classical role of arrestins is considered to be the internalization and desensitization of GPCRs, more recent studies suggest that arrestins can serve as scaffolds to recruit phosphatidyl inositol-3 kinases (PI3K)s to Gq-coupled receptors and promote PI3K-dependent signaling. Thrombin stimulates the PI3K-dependent activation of Akt in platelets in a Gq-dependent manner. Therefore, we sought to determine whether arrestins are involved in the PI3K-dependent activation of Akt in platelets. Comparative immunoblots show that of the two non-visual mammalian arrestins, only one, arrestin-2 (β-arrestin-1), is expressed in human and mouse platelets. Immunoprecipitation of arrestin-2 or p85-PI3K from platelet lysates demonstrated that arrestin-2 associates with the p85 subunit of PI3Ka/b in thrombin or ADP-stimulated platelets, but not resting cells. The association can be inhibited by inhibitors of the P2Y12 receptor for ADP, but not by P2Y1 inhibitors. p85-arrestin association is also blocked by inhibitors of src family kinases, as is Akt phosphorylation. To determine whether src family members were part of the p85-arrestin complexes, immunoblots were re-probed with antibodies to src, lyn and fyn. The results show that Lyn is incorporated into thrombin-stimulated arrestin complexes in a P2Y12-dependent manner. To determine whether arrestin-2 is important for Akt phosphorylation in platelets, megakaryocytes differentiated in culture from mouse embryonic stem cells were used as models of platelet signaling, since these cells are amenable to genetic manipulation. Arrestin-2 was inhibited in the cultured megakaryocytes using a siRNA approach, then cells were stimulated with thrombin and Akt phosphorylation was assessed by immunoblotting. Arrestin-2 expression in the cultured megakaryocytes treated with arrestin-2 specific siRNA was suppressed by an average of 53% compared to cells treated with scrambled siRNA, while thrombin-stimulated Akt phosphorylation was suppressed by 98% compared to scrambled siRNA-treated control cells (n=3 experiments, difference is significant, p=.01, unpaired student’s t-test). In conclusion, the results show that arrestin-2, lyn and PI3Kform a tri-molecular complex following stimulation of platelets with ADP or thrombin. Formation of arrestin complexes at activated receptor sites is important for the localized recruitment and src-dependent activation of p85-PI3K, thus promoting activation of Akt by G protein-coupled receptors.

scholarly journals Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor

2012 ◽  
Vol 108 (5) ◽  
pp. 1473-1483 ◽  
Author(s):  
Chao Li ◽  
Xian Xuan Chi ◽  
Wenrui Xie ◽  
J. A. Strong ◽  
J.-M. Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Neuronal Excitability ◽  
Small Diameter ◽  
G Protein Coupled Receptors ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Previously we demonstrated that sphingosine 1-phosphate receptor 1 (S1PR1) played a prominent, but not exclusive, role in enhancing the excitability of small-diameter sensory neurons, suggesting that other S1PRs can modulate neuronal excitability. To examine the potential role of S1PR2 in regulating neuronal excitability we used the established selective antagonist of S1PR2, JTE-013. Here we report that exposure to JTE-013 alone produced a significant increase in excitability in a time- and concentration-dependent manner in 70–80% of recorded neurons. Internal perfusion of sensory neurons with guanosine 5′- O-(2-thiodiphosphate) (GDP-β-S) via the recording pipette inhibited the sensitization produced by JTE-013 as well as prostaglandin E2. Pretreatment with pertussis toxin or the selective S1PR1 antagonist W146 blocked the sensitization produced by JTE-013. These results indicate that JTE-013 might act as an agonist at other G protein-coupled receptors. In neurons that were sensitized by JTE-013, single-cell RT-PCR studies demonstrated that these neurons did not express the mRNA for S1PR2. In behavioral studies, injection of JTE-013 into the rat's hindpaw produced a significant increase in the mechanical sensitivity in the ipsilateral, but not contralateral, paw. Injection of JTE-013 did not affect the withdrawal latency to thermal stimulation. Thus JTE-013 augments neuronal excitability independently of S1PR2 by unknown mechanisms that may involve activation of other G protein-coupled receptors such as S1PR1. Clearly, further studies are warranted to establish the causal nature of this increased sensitivity, and future studies of neuronal function using JTE-013 should be interpreted with caution.

Anti-proliferative potential of cyclotetrapeptides from Bacillus velezensis RA5401 and their molecular docking on G-Protein-Coupled Receptors

2018 ◽  
Vol 123 ◽  
pp. 419-425 ◽  
Author(s):  
Najeeb Ur Rehman ◽  
Raeid M.M. Abed ◽  
Hidayat Hussain ◽  
Husain Yar Khan ◽  
Ajmal Khan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Proliferative Potential ◽  
Bacillus Velezensis ◽  
G Protein Coupled

NPY, ET-1, and Ang II nuclear receptors in human endocardial endothelial cellsThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 299-307 ◽  
Author(s):  
Danielle Jacques ◽  
Sawsan Sader ◽  
Claudine Perreault ◽  
Dima Abdel-Samad ◽  
Farah Jules ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Ang Ii ◽  
Special Issue ◽  
A Cell ◽  
Endocardial Endothelial Cells ◽  
Plasma Membrane Receptors ◽  
G Protein Coupled ◽  
Selection Of

Neuropeptide Y (NPY), endothelin-1 (ET-1), and angiotensin II (Ang II) are peptides that are known to play many important roles in cardiovascular homeostasis. The physiological actions of these peptides are thought to be primarily mediated by plasma membrane receptors that belong to the G-protein-coupled receptor superfamily. However, there is increasing evidence that suggests the existence of functional G-protein-coupled receptors at the level of the nucleus and that the nucleus could be a cell within a cell. Here, we review our work showing the presence in the nucleus of the NPY Y1 receptor, the ETA and ETB receptors, as well as the AT1 and AT2 receptors and their respective ligands. This work was carried out in 20-week-old fetal human endocardial endothelial cells. Our results demonstrate that nuclear Y1, AT1, and ETA receptors modulate nuclear calcium in these cells.

scholarly journals Towards deorphanizing G protein-coupled receptors of Schistosoma mansoni using the MALAR yeast two-hybrid system

Parasitology ◽  
2019 ◽  
Vol 147 (8) ◽  
pp. 865-872 ◽  
Author(s):  
Oliver Weth ◽  
Simone Haeberlein ◽  
Martin Haimann ◽  
Yinjie Zhang ◽  
Christoph G. Grevelding
Keyword(s):  
Schistosoma Mansoni ◽  
G Protein ◽  
Hybrid System ◽  
G Protein Coupled Receptors ◽  
Dependent Manner ◽  
Yeast Two Hybrid ◽  
Ligand Interaction ◽  
Yeast Two Hybrid System ◽  
G Protein Coupled ◽  
Two Hybrid

AbstractSchistosomiasis is an acute and chronic disease caused by parasitic worms of the genus Schistosoma. Treatment is solely dependent on praziquantel. In the face of the worldwide dimension, projects have been initiated to develop new chemotherapies. Due to their proven druggability, G protein-coupled receptors (GPCRs) are promising targets for anthelmintics. However, to identify candidate receptors, a deeper understanding of GPCR signalling in schistosome biology is essential. Comparative transcriptomics of paired and unpaired worms and their gonads revealed 59 differentially regulated GPCR-coding genes putatively involved in neuronal processes. In general, the diversity among GPCRs and their integral membrane topology make it difficult to characterize and deorphanize these receptors. To overcome existing limitations, we performed a pilot approach and utilized the innovative Membrane-Anchored Ligand And Receptor yeast two-hybrid system (MALAR-Y2H) to associate potential neuropeptide ligands with their cognate receptors. Here, we demonstrated the ability to express full-length GPCRs of Schistosoma mansoni in a heterologous yeast-based system. Additionally, we localized GPCRs and chimeras of neuropeptides fused to the WBP1 transmembrane domain of yeast to the plasma membrane of yeast cells. Reporter gene assays indicated ligand-receptor binding, which allowed us to identify certain neuropeptides as potential ligands for two GPCRs, which had been found before to be differentially expressed in schistosomes in a pairing-dependent manner. Thus, the MALAR-Y2H system appears suitable to unravel schistosome GPCR–ligand interactions. Besides its relevance for understanding schistosome biology, identifying and characterizing GPCR–ligand interaction will also contribute to applied research aspects.

scholarly journals Lysine63-linked ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia

2020 ◽  
Author(s):  
Swapnil Rohidas Shinde ◽  
Andrew R. Nager ◽  
Maxence V. Nachury
Keyword(s):  
G Protein ◽  
Somatostatin Receptor ◽  
G Protein Coupled Receptors ◽  
Dependent Manner ◽  
Bardet Biedl Syndrome ◽  
Ubiquitinated Proteins ◽  
Molecular Sensor ◽  
Regulated Trafficking ◽  
G Protein Coupled ◽  
Orphan Gpcr

ABSTRACTRegulated trafficking of G-protein coupled receptors (GPCRs) controls cilium-based signaling pathways. β-arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl Syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with K63-linked ubiquitin (K63Ub) chains in a β-arrestin-dependent manner prior to BBSome-mediated exit. Removal of ubiquitin acceptor residues from the somatostatin receptor 3 (SSTR3) and from the orphan GPCR GPR161 demonstrates that ubiquitination of ciliary GPCRs is required for their regulated exit from cilia. Furthermore, targeting a K63Ub-specific deubiquitinase to cilia blocks the exit of GPR161, SSTR3 and Smoothened (SMO) from cilia. Finally, ubiquitinated proteins accumulate in cilia of mammalian photoreceptors and Chlamydomonas cells when BBSome function is compromised. We conclude that K63Ub chains mark GPCRs and other unwanted ciliary proteins for recognition by the ciliary exit machinery.

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