scholarly journals Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors

2020 ◽  
Vol 3 (2) ◽  
pp. 246-262 ◽  
Author(s):  
Michael L. Garelja ◽  
Maggie Au ◽  
Margaret A. Brimble ◽  
Joseph J. Gingell ◽  
Erica R. Hendrikse ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Gpcr Activation ◽  
Class B ◽  
Class B Gpcr

Class-B GPCR activation: is ligand helix-capping the key?

2008 ◽  
Vol 33 (7) ◽  
pp. 314-319 ◽  
Author(s):  
Jean-Michel Neumann ◽  
Alain Couvineau ◽  
Samuel Murail ◽  
Jean-Jacques Lacapère ◽  
Nadège Jamin ◽  
...  
Keyword(s):  
Gpcr Activation ◽  
Helix Capping ◽  
Class B ◽  
Class B Gpcr

scholarly journals Exogenous Promoter Triggers APETALA3 Silencing through RNA-Directed DNA Methylation Pathway in Arabidopsis

2019 ◽  
Vol 20 (18) ◽  
pp. 4478 ◽  
Author(s):  
Benqi Wang ◽  
Jie Liu ◽  
Lei Chu ◽  
Xue Jing ◽  
Huadong Wang ◽  
...  
Keyword(s):  
Transgenic Plants ◽  
Molecular Mechanisms ◽  
Plant Reproduction ◽  
Vital Role ◽  
Abnormal Development ◽  
Class A ◽  
Methylation Pathway ◽  
Class B ◽  
Transgenic Lines ◽  
Morphological Defects

The development of floral organs plays a vital role in plant reproduction. In our research, the APETALA3 (AP3) promoter-transgenic lines showed abnormal developmental phenotypes in stamens and petals. The aim of this study is to understand the molecular mechanisms of the morphological defects in transgenic plants. By performing transgenic analysis, it was found that the AP3-promoted genes and the vector had no relation to the morphological defects. Then, we performed the expression analysis of the class A, B, and C genes. A dramatic reduction of transcript levels of class B genes (AP3 and PISTILLATA) was observed. Additionally, we also analyzed the methylation of the promoters of class B genes and found that the promoter of AP3 was hypermethylated. Furthermore, combining mutations in rdr2-2, drm1/2, and nrpd1b-11 with the AP3-silencing lines rescued the abnormal development of stamens and petals. The expression of AP3 was reactivated and the methylation level of AP3 promoter was also reduced in RdDM-defective AP3-silencing lines. Our results showed that the RdDM pathway contributed to the transcriptional silencing in the transgenic AP3-silencing lines. Moreover, the results revealed that fact that the exogenous fragment of a promoter could trigger the methylation of homologous endogenous sequences, which may be ubiquitous in transgenic plants.

FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs

2018 ◽  
Vol 11 (559) ◽  
pp. eaar5536 ◽  
Author(s):  
Shane C. Wright ◽  
Maria Consuelo Alonso Cañizal ◽  
Tobias Benkel ◽  
Katharina Simon ◽  
Christian Le Gouill ◽  
...  
Keyword(s):  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Group Of Seven ◽  
Stem Cell Regulation ◽  
Wnt Proteins ◽  
Gpcr Activation ◽  
Class B ◽  
Activation Profile ◽  
Functional Inactivation ◽  
Class F

Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)–based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

scholarly journals Crystal Structure of the Ectodomain Complex of the CGRP Receptor, a Class-B GPCR, Reveals the Site of Drug Antagonism

Structure ◽  
2010 ◽  
Vol 18 (9) ◽  
pp. 1083-1093 ◽  
Author(s):  
Ernst ter Haar ◽  
Christopher M. Koth ◽  
Norzehan Abdul-Manan ◽  
Lora Swenson ◽  
Joyce T. Coll ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cgrp Receptor ◽  
Class B ◽  
Drug Antagonism ◽  
Class B Gpcr

scholarly journals Gq/11-dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

2020 ◽  
Vol 117 (13) ◽  
pp. 7455-7460 ◽  
Author(s):  
Alex D. White ◽  
Frederic G. Jean-Alphonse ◽  
Fei Fang ◽  
Karina A. Peña ◽  
Shi Liu ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Camp Production ◽  
Spatiotemporal Regulation ◽  
Camp Generation ◽  
Early Endosomes ◽  
Class B ◽  
Phosphoinositide 3 Kinase

cAMP production upon activation of Gs by G protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mechanisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gαq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gβγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR–βarrestin–Gβγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.

Structure of class B GPCR corticotropin-releasing factor receptor 1

Nature ◽  
2013 ◽  
Vol 499 (7459) ◽  
pp. 438-443 ◽  
Author(s):  
Kaspar Hollenstein ◽  
James Kean ◽  
Andrea Bortolato ◽  
Robert K. Y. Cheng ◽  
Andrew S. Doré ◽  
...  
Keyword(s):  
Corticotropin Releasing Factor ◽  
Class B ◽  
Class B Gpcr

scholarly journals Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

2017 ◽  
Vol 31 (6) ◽  
pp. 2603-2611 ◽  
Author(s):  
Ying Li ◽  
Xuemin Zheng ◽  
Xiulin Yi ◽  
Changxiao Liu ◽  
Dexin Kong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Natural Class ◽  
Class B ◽  
Class B Gpcr

An insight into antagonist binding and induced conformational dynamics of class B GPCR corticotropin-releasing factor receptor 1

2015 ◽  
Vol 11 (7) ◽  
pp. 2042-2050 ◽  
Author(s):  
Junli Xu ◽  
Zhonghua Wang ◽  
Pi Liu ◽  
Dongmei Li ◽  
Jianping Lin
Keyword(s):  
Small Molecule ◽  
Conformational Dynamics ◽  
Corticotropin Releasing Factor ◽  
Class B ◽  
Antagonist Binding ◽  
Insight Into ◽  
Class B Gpcr

The binding of small-molecule antagonists, CP-376395 and MTIP, would induce conformational dynamics behaviors of CRF1R.

scholarly journals Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells

2017 ◽  
Vol 312 (4) ◽  
pp. C428-C437 ◽  
Author(s):  
Nathaniel G. dela Paz ◽  
Benoît Melchior ◽  
John A. Frangos
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Fluid Shear Stress ◽  
Receptor Activation ◽  
Proximity Ligation Assay ◽  
Human Coronary Artery ◽  
Gpcr Activation ◽  
G Protein Coupled

Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/Gαq/11 pair in EC shear stress-induced mechanotransduction. We demonstrated that sphingosine 1-phosphate (S1P) stimulation causes a rapid dissociation at 0.5 min of Gαq/11 from its receptor S1P3, followed by an increased association within 2 min of GPCR kinase-2 (GRK2) and β-arrestin-1/2 with S1P3 in human coronary artery ECs, which are consistent with GPCR/Gαq/11 activation and receptor desensitization/internalization. The G protein activator AlF4 resulted in increased dissociation of Gαq/11 from S1P3, but no increase in association between S1P3 and either GRK2 or β-arrestin-1/2. The G protein inhibitor guanosine 5′-(β-thio) diphosphate (GDP-β-S) and the S1P3 antagonist VPC23019 both prevented S1P-induced activation. Shear stress also caused the rapid activation within 7 s of S1P3/Gαq/11. There were no increased associations between S1P3 and GRK2 or S1P3 and β-arrestin-1/2 until 5 min. GDP-β-S, but not VPC23019, prevented dissociation of Gαq/11 from S1P3 in response to shear stress. Shear stress did not induce rapid dephosphorylation of β-arrestin-1 or rapid internalization of S1P3, indicating no GPCR activation. These findings suggest that Gαq/11 participates in the sensing/transducing of shear stress independently of GPCR activation in ECs.

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