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 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 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 Analysis of Protein Complex Formation on Membrane Surfaces by Single Molecule Diffusion

2012 ◽  
Vol 102 (3) ◽  
pp. 183a
Author(s):  
Brian P. Ziemba ◽  
Jefferson D. Knight ◽  
Joseph J. Falke
Keyword(s):  
Complex Formation ◽  
Single Molecule ◽  
Protein Complex ◽  
Membrane Surfaces ◽  
Protein Complex Formation

scholarly journals Targeting WNT10B-Driven Signalling through Induction of FZD6 By Porcupine Inhibition in T Cell Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3956-3956
Author(s):  
Adriana Cassaro ◽  
Francesca Lazzaroni ◽  
Giovanni Grillo ◽  
Gianluigi Reda ◽  
Roberto Cairoli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Complex Formation ◽  
Wnt Signaling ◽  
Protein Complex ◽  
Lymphoblastic Leukemia ◽  
Protein Complex Formation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Short Hairpin ◽  
Signaling Activation

Background Wnt/Fzd signaling is known to play a pervasive influence in hematopoietic stem cell maintenance, T-cell development in the thymus and function as well as an important role in T-cell acute lymphoblastic leukemia (T-ALL) establishment. We have previously described a recurrent rearrangement involving the WNT10Blocus (WNT10BR) expressing a transcript variant (WNT10BIVS1) in acute myeloid leukemia. To determine the occurrence of this rearrangement in T-ALL we analyzed retrospectively an italian cohort of patients (n=20) and detected the WNT10BRrearrangement with a high prevalence (14/20). We also confirmed the relevance of these findings to human disease, detecting the molecular circuit triggered by the WNT10B over-expression using the MOLT-4 T-ALL cell model.In this report, we examined the expression of components of the Wnt signaling cascade mediated by WNT10B and the effects of specific gene silencing by short hairpin RNA (shRNA) and exposure to the potent PORCN inhibitor (LGK974), or the TGFbRI inhibitor (A83-01) on the WNT10B-mediated Wnt signaling activation. Methods We used the T-ALL model MOLT-4 cell line to assess the WNT10B/FZD signaling axis driven by WNT10BR. In order to identify interaction between WNT10B and FZD receptors we performed in situ proximity ligation assay (PLA) a method used to visualize protein-protein interactions.MOLT4 cells were infected with WNT10B/WNT10BIVS1-shRNA silencing lentiviral vectors versus empty vector control and treated with increased concentration of LGK974 or A83-01, subsequently the effects of pharmacological inhibition on the WNT10B/FZD interactions and on Wnt effector proteins were evaluated by PLA and expression analyses. Cell proliferation and cell death were measured by EdU assay and Annexin-V/Propidium Iodide (PI) analyses. Results We found that WNT10BRdrives Wnt signaling activity in T-ALL through interaction of WNT10B with FZD6 receptor. The effects of WNT10B/FZD6 interaction on Wnt-mediated signal in MOLT-4 were interfered by short hairpin RNAs (shRNAs)-mediated gene silencing and by small molecules-mediated disruption of Wnt-dependent signaling. We performed WNT10BIVS1knockdown or pharmacological inhibition of WNT10B release by the porcupine (PORCN) inhibitor LGK974 and these in turn progressively down-modulate WNT10B/FZD6 protein complex formation and significantly impairs intracellular effectors and leukemic expansion. Finally, we induced interference to the WNT10B/FZD6 protein complex formation by exposure to the TGFbRI inhibitor A83-01 via inhibiting FZD6 expression, confirming its role in the WNT10B-mediated signaling activation. Conclusion Our study describes the molecular circuit of WNT10BR-mediated activation and highlight a strategy for a major improvement in T-ALL treatment.By altering FZD6-WNT10B complex formation, may provide the basis for therapeutic strategies to eradicate leukemic stem cells in patients selectively deployed depending on the underlying genetics of disease. Disclosures No relevant conflicts of interest to declare.

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