scholarly journals Pathological AT1R-B2R Protein Aggregation and Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2609
Author(s):  
Ursula Quitterer ◽  
Said AbdAlla
Keyword(s):  
Risk Factors ◽  
Complex Formation ◽  
Protein Aggregation ◽  
G Protein ◽  
Protein Complex ◽  
G Protein Coupled Receptors ◽  
Protein Complex Formation ◽  
The Impact ◽  
G Protein Coupled ◽  
Gpcr Protein

Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and life-saving treatment to alleviate symptoms of preeclampsia because a causative treatment does not exist, which could prolong a pregnancy complicated with preeclampsia. Preeclampsia is a complex medical condition, which is attributed to a variety of different risk factors and causes. Risk factors account for insufficient placentation and impaired vasculogenesis and finally culminate in this life-threatening condition of pregnancy. Despite progress, many pathomechanisms and causes of preeclampsia are still incompletely understood. In recent years, it was found that excessive protein complex formation between G-protein-coupled receptors is a common sign of preeclampsia. Specifically, the aberrant heteromerization of two vasoactive G-protein-coupled receptors (GPCRs), the angiotensin II AT1 receptor and the bradykinin B2 receptor, is a causative factor of preeclampsia symptoms. Based on this knowledge, inhibition of abnormal GPCR protein complex formation is an experimental treatment approach of preeclampsia. This review summarizes the impact of pathological GPCR protein aggregation on symptoms of preeclampsia and delineates potential new therapeutic targets.

scholarly journals S  (+)-Ketamine Suppresses Desensitization of γ-Aminobutyric Acid Type B Receptor-mediated Signaling by Inhibition of the Interaction of γ-Aminobutyric Acid Type B Receptors with G Protein–coupled Receptor Kinase 4 or 5

2011 ◽  
Vol 114 (2) ◽  
pp. 401-411 ◽  
Author(s):  
Yuko Ando ◽  
Minoru Hojo ◽  
Masato Kanaide ◽  
Masafumi Takada ◽  
Yuka Sudo ◽  
...  
Keyword(s):  
Complex Formation ◽  
G Protein ◽  
Protein Complex ◽  
Protein Complexes ◽  
Aminobutyric Acid ◽  
K Channel ◽  
Type B ◽  
Protein Complex Formation ◽  
Acid Type ◽  
G Protein Coupled

Background Intrathecal baclofen therapy is an established treatment for severe spasticity. However, long-term management occasionally results in the development of tolerance. One of the mechanisms of tolerance is desensitization of γ-aminobutyric acid type B receptor (GABABR) because of the complex formation of the GABAB2 subunit (GB2R) and G protein-coupled receptor kinase (GRK) 4 or 5. The current study focused on S(+)-ketamine, which reduces the development of morphine tolerance. This study was designed to investigate whether S(+)-ketamine affects the GABABR desensitization processes by baclofen. Methods The G protein-activated inwardly rectifying K channel currents induced by baclofen were recorded using Xenopus oocytes coexpressing G protein-activated inwardly rectifying K channel 1/2, GABAB1a receptor subunit, GB2R, and GRK. Translocation of GRKs 4 and 5 and protein complex formation of GB2R with GRKs were analyzed by confocal microscopy and fluorescence resonance energy transfer analysis in baby hamster kidney cells coexpressing GABAB1a receptor subunit, fluorescent protein-tagged GB2R, and GRKs. The formation of protein complexes of GB2R with GRKs was also determined by coimmunoprecipitation and Western blot analysis. Results Desensitization of GABABR-mediated signaling was suppressed by S(+)-ketamine in a concentration-dependent manner in the electrophysiologic assay. Confocal microscopy revealed that S(+)-ketamine inhibited translocation of GRKs 4 and 5 to the plasma membranes and protein complex formation of GB2R with the GRKs. Western blot analysis also showed that S(+)-ketamine inhibited the protein complex formation of GB2R with the GRKs. Conclusion S(+)-Ketamine suppressed the desensitization of GABABR-mediated signaling at least in part through inhibition of formation of protein complexes of GB2R with GRK 4 or 5.

scholarly journals Structural Insights into the Process of GPCR-G Protein Complex Formation

Cell ◽  
2019 ◽  
Vol 177 (5) ◽  
pp. 1243-1251.e12 ◽  
Author(s):  
Xiangyu Liu ◽  
Xinyu Xu ◽  
Daniel Hilger ◽  
Philipp Aschauer ◽  
Johanna K.S. Tiemann ◽  
...  
Keyword(s):  
Complex Formation ◽  
G Protein ◽  
Protein Complex ◽  
Protein Complex Formation ◽  
Structural Insights

scholarly journals Fungal G-Protein-Coupled Receptors: A Promising Mediator of the Impact of Extracellular Signals on Biosynthesis of Ochratoxin A

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Gao ◽  
Xinge Xu ◽  
Kunlun Huang ◽  
Zhihong Liang
Keyword(s):  
G Protein ◽  
Ochratoxin A ◽  
G Protein Coupled Receptors ◽  
Aspergillus Ochraceus ◽  
Transmembrane Receptors ◽  
Environmental Signals ◽  
Extracellular Signals ◽  
Fungal Biology ◽  
The Impact ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are transmembrane receptors involved in transducing signals from the external environment inside the cell, which enables fungi to coordinate cell transport, metabolism, and growth to promote their survival, reproduction, and virulence. There are 14 classes of GPCRs in fungi involved in sensing various ligands. In this paper, the synthesis of mycotoxins that are GPCR-mediated is discussed with respect to ligands, environmental stimuli, and intra-/interspecific communication. Despite their apparent importance in fungal biology, very little is known about the role of ochratoxin A (OTA) biosynthesis by Aspergillus ochraceus and the ligands that are involved. Fortunately, increasing evidence shows that the GPCR that involves the AF/ST (sterigmatocystin) pathway in fungi belongs to the same genus. Therefore, we speculate that GPCRs play an important role in a variety of environmental signals and downstream pathways in OTA biosynthesis. The verification of this inference will result in a more controllable GPCR target for control of fungal contamination in the future.

scholarly journals High-mass MALDI-MS unravels ligand-mediated G protein–coupling selectivity to GPCRs

2021 ◽  
Vol 118 (31) ◽  
pp. e2024146118
Author(s):  
Na Wu ◽  
Agnieszka M. Olechwier ◽  
Cyrill Brunner ◽  
Patricia C. Edwards ◽  
Ching-Ju Tsai ◽  
...  
Keyword(s):  
Complex Formation ◽  
G Protein ◽  
High Sensitivity ◽  
Maldi Ms ◽  
High Mass ◽  
Ionization Mass ◽  
Binding Affinities ◽  
C Terminus ◽  
Protein Complex Formation ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are important pharmaceutical targets for the treatment of a broad spectrum of diseases. Although there are structures of GPCRs in their active conformation with bound ligands and G proteins, the detailed molecular interplay between the receptors and their signaling partners remains challenging to decipher. To address this, we developed a high-sensitivity, high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) method to interrogate the first stage of signal transduction. GPCR–G protein complex formation is detected as a proxy for the effect of ligands on GPCR conformation and on coupling selectivity. Over 70 ligand–GPCR–partner protein combinations were studied using as little as 1.25 pmol protein per sample. We determined the selectivity profile and binding affinities of three GPCRs (rhodopsin, beta-1 adrenergic receptor [β1AR], and angiotensin II type 1 receptor) to engineered Gα-proteins (mGs, mGo, mGi, and mGq) and nanobody 80 (Nb80). We found that GPCRs in the absence of ligand can bind mGo, and that the role of the G protein C terminus in GPCR recognition is receptor-specific. We exemplified our quantification method using β1AR and demonstrated the allosteric effect of Nb80 binding in assisting displacement of nadolol to isoprenaline. We also quantified complex formation with wild-type heterotrimeric Gαiβγ and β-arrestin-1 and showed that carvedilol induces an increase in coupling of β-arrestin-1 and Gαiβγ to β1AR. A normalization strategy allows us to quantitatively measure the binding affinities of GPCRs to partner proteins. We anticipate that this methodology will find broad use in screening and characterization of GPCR-targeting drugs.

Glucagon counteracts interleukin-6-dependent gene expression by redundant action of Epac and PKA

2011 ◽  
Vol 392 (12) ◽  
pp. 1123-1134 ◽  
Author(s):  
Christina Khouri ◽  
Anna Dittrich ◽  
Sara Dutton Sackett ◽  
Bernd Denecke ◽  
Christian Trautwein ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Biological Response ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Counterregulatory Hormones ◽  
The Impact ◽  
G Protein Coupled

AbstractInflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target geneTfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response.

scholarly journals Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

2016 ◽  
Vol 9 (3) ◽  
pp. 318-329 ◽  
Author(s):  
Nader Alaridah ◽  
Nataliya Lutay ◽  
Erik Tenland ◽  
Anna Rönnholm ◽  
Oskar Hallgren ◽  
...  
Keyword(s):  
G Protein ◽  
Airway Epithelial Cells ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Airway Epithelial ◽  
Mucosal Vaccination ◽  
Mapk Signalling Pathway ◽  
The Impact ◽  
G Protein Coupled ◽  
Rac1 Expression

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

scholarly journals Molecular Determinants of GPCR-G Protein Complex Formation

2012 ◽  
Vol 102 (3) ◽  
pp. 31a-32a
Author(s):  
Tarjani M. Thaker ◽  
Ali I. Kaya ◽  
Anita M. Preininger ◽  
Heidi E. Hamm ◽  
T.M. Iverson
Keyword(s):  
Complex Formation ◽  
G Protein ◽  
Protein Complex ◽  
Protein Complex Formation ◽  
Molecular Determinants

scholarly journals Novel Computational Methodologies for Structural Modeling of Spacious Ligand Binding Sites of G-Protein-Coupled Receptors: Development and Application to Human Leukotriene B4 Receptor

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yoko Ishino ◽  
Takanori Harada
Keyword(s):  
G Protein ◽  
Time Scale ◽  
Thermal Fluctuations ◽  
Leukotriene B4 ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Leukotriene B4 Receptor ◽  
G Protein Coupled ◽  
Gpcr Protein

This paper describes a novel method to predict the activated structures of G-protein-coupled receptors (GPCRs) with high accuracy, while aiming for the use of the predicted 3D structures inin silicovirtual screening in the future. We propose a new method for modeling GPCR thermal fluctuations, where conformation changes of the proteins are modeled by combining fluctuations on multiple time scales. The core idea of the method is that a molecular dynamics simulation is used to calculate average 3D coordinates of all atoms of a GPCR protein against heat fluctuation on the picosecond or nanosecond time scale, and then evolutionary computation including receptor-ligand docking simulations functions to determine the rotation angle of each helix of a GPCR protein as a movement on a longer time scale. The method was validated using human leukotriene B4 receptor BLT1 as a sample GPCR. Our study demonstrated that the proposed method was able to derive the appropriate 3D structure of the active-state GPCR which docks with its agonists.

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