Adhesion‐GPCR Gpr116 (ADGRF5) is a Regulator of Urine Acidification

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Nathan Zaidman ◽  
Viktor Tomilin ◽  
Mahendra Damarla ◽  
Josephine Tidmore ◽  
Oleh Pochynyuk ◽  
...  
Keyword(s):  
Urine Acidification ◽  
Adhesion Gpcr

scholarly journals Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David M. Favara ◽  
Ines Liebscher ◽  
Ali Jazayeri ◽  
Madhulika Nambiar ◽  
Helen Sheldon ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Gc Content ◽  
Luciferase Reporter ◽  
Cell Phenotype ◽  
Beta Catenin ◽  
Sprouting Angiogenesis ◽  
Proteolytic Site ◽  
Elevated Expression ◽  
Adhesion Gpcr

AbstractADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.

scholarly journals Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anastasia Georgiadi ◽  
Valeria Lopez-Salazar ◽  
Rabih El- Merahbi ◽  
Rhoda Anane Karikari ◽  
Xiaochuan Ma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Dependent Manner ◽  
Metabolic Dysfunction ◽  
Functional Interaction ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Obesity And Diabetes ◽  
Adhesion Gpcr ◽  
Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

The Adhesion GPCR CD97/ADGRE5 inhibits apoptosis

2015 ◽  
Vol 65 ◽  
pp. 197-208 ◽  
Author(s):  
Cheng-Chih Hsiao ◽  
Kerstin Keysselt ◽  
Hsin-Yi Chen ◽  
Doreen Sittig ◽  
Jörg Hamann ◽  
...  
Keyword(s):  
Adhesion Gpcr

scholarly journals A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity

2017 ◽  
Vol 38 (12) ◽  
pp. 1751-1760 ◽  
Author(s):  
Ryan H. Purcell ◽  
Camilo Toro ◽  
William A. Gahl ◽  
Randy A. Hall
Keyword(s):  
Receptor Signaling ◽  
Adhesion Gpcr ◽  
Signaling Activity

scholarly journals Constitutive signaling by the C-terminal fragment of polycystin-1 is mediated by a tethered peptide agonist

2021 ◽  
Author(s):  
Brenda S Magenheimer ◽  
Ericka Nevarez Munoz ◽  
Jayalakshmi Ravichandran ◽  
Robin L Maser
Keyword(s):  
G Protein ◽  
Transmembrane Domain ◽  
Missense Mutations ◽  
Protein Signaling ◽  
Gene Encoding ◽  
Reporter Assays ◽  
Autosomal Dominant Polycystic Kidney ◽  
Signaling Activation ◽  
Peptide Agonist ◽  
Adhesion Gpcr

Mutation of the PKD1 gene, encoding polycystin-1 (PC1), is the primary cause of autosomal dominant polycystic kidney disease. PC1 is an 11-transmembrane domain protein that binds and modulates the activity of multiple heterotrimeric G protein families and is thought to function as a non-canonical G protein-coupled receptor (GPCR). PC1 shares a conserved GPCR autoproteolysis inducing (GAIN) domain with the adhesion family of GPCRs, that promotes an auto-catalytic, cis-cleavage at the GPCR proteolysis site (GPS) located proximal to the first transmembrane domain. GPS cleavage divides these receptors into two associated subunits, the extracellular N-terminal (NTF) and transmembrane C-terminal (CTF) fragments. For the adhesion GPCRs, removal of the NTF leads to activation of G protein signaling as a result of the exposure and subsequent intramolecular binding of the extracellular N-terminal stalk of the CTF, i.e., the tethered cryptic ligand or tethered agonist model. Here, we test the hypothesis that PC1-mediated signaling is regulated by an adhesion GPCR-like, tethered agonist mechanism. Using cell-based reporter assays and mutagenesis of PC1 expression constructs, we show that the CTF form of PC1 requires the stalk for signaling activation and synthetic peptides derived from the PC1 stalk sequence can re-activate signaling by a stalk-less CTF. In addition, we demonstrate that ADPKD-associated missense mutations within the PC1 stalk affect signaling and can inhibit GPS cleavage. These results provide a foundation for beginning to understand the molecular mechanism of G protein regulation by PC1 and suggest that a tethered agonist-mediated mechanism can contribute to PKD pathogenesis.

scholarly journals Urine Acidification After Ammonium Chloride

2018 ◽  
Vol 72 (6) ◽  
pp. 909-911
Author(s):  
Anneke P. Bech ◽  
Tom Nijenhuis ◽  
Jack F.M. Wetzels
Keyword(s):  
Ammonium Chloride ◽  
Urine Acidification

USE OF HEMODIALYSIS IN THE TREATMENT OF QUINIDINE POISONING

PEDIATRICS ◽  
1973 ◽  
Vol 52 (1) ◽  
pp. 95-99
Author(s):  
Ekkehard W. Reimold ◽  
Walter J. Reynolds ◽  
David E. Fixler ◽  
LaVerne McElroy
Keyword(s):  
Blood Flow ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Treatment Period ◽  
Filtration Rate ◽  
Renal Excretion ◽  
Artificial Kidney ◽  
Flow Rates ◽  
Urine Acidification ◽  
Forced Diuresis

Hemodialysis was used in addition to forced diuresis in the treatment of quinidine poisoning of a 3-year-old girl. The estimated retained dose of quinidine was 1,600 mg. During a 36-hour treatment period the patient excreted through the kidneys 768.1 mg quinidine (21.3 mg/hr). Hemodialysis almost doubled the quinidine elimination by removing 145 mg in eight hours (18.1 mg/hr): renal excretion, 55%; hemodialysis, 45%. The quinidine elimination with dialysis is high when high blood flow rates through the artificial kidney can be maintained. Adequate glomerular filtration rate and urine acidification are necessary for high renal excretion of quinidine.

CSIG-25. BAI1/ADGRB1 REGULATES TGFβ1-INDUCED MESENCHYMAL SWITCH IN MEDULLOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi38-vi39
Author(s):  
Satoru Osuka ◽  
Liquan Yang ◽  
Dan Zhu ◽  
Hideharu Hashimoto ◽  
Erwin G Van Meir
Keyword(s):  
Brain Tumor ◽  
Tumor Invasion ◽  
Angiogenesis Inhibitor ◽  
Leptomeningeal Metastasis ◽  
Epigenetic Silencing ◽  
Normal Brain ◽  
Molecular Defects ◽  
Poor Outcome ◽  
Pathway Activation ◽  
Adhesion Gpcr

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. MB tends to metastasize to the brain meninges and subarachnoid space and the spinal cord. Leptomeningeal metastasis is frequently found at initial diagnosis and leads to tumor relapse after standard treatment. Leptomeningeal metastasis remains a major challenge and is related with poor outcome. Acquiring a better knowledge of molecular defects underlying metastatic disease is essential for the development of effective therapies. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is a transmembrane receptor of the adhesion GPCR family widely expressed in normal brain, but its expression is lost in the majority of medulloblastoma through epigenetic silencing. We reported that BAI1 protects p53 from Mdm2-mediated degradation and regulate tumor growth in medulloblastoma (Zhu D. et al, Cancer Cell, 2018). However, it is unclear whether BAI1 loss is important for tumor invasion and the mesenchymal phenotype in MB. Microarray analysis of the published MB dataset revealed that low BAI1 mRNA expression correlates with poor outcome and with expression of many key mesenchymal genes, including Fibronectin1, SLUG, and TWIST1. Restoration of BAI1 expression in human MB cells suppresses mesenchymal gene expression in culture, and dramatically decreases brain tumor invasion. Mechanistically, we found that the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in MB cells by methylated CpG-binding protein MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that restoration of BAI1 expression by KCC-07 treatment dramatically reduced tumor cell invasion of MB cells. These experiments demonstrate that epigenetic silencing of BAI1 is important for activation of the MB invasive phenotype through TGFβ1 pathway activation. Epigenetic targeting of this process by KCC-07 can reduce MB invasion.

Designer adhesion GPCR tells its signaling story

2020 ◽  
Vol 16 (12) ◽  
pp. 1280-1281
Author(s):  
Eugenia V. Gurevich ◽  
Vsevolod V. Gurevich
Keyword(s):  
Adhesion Gpcr
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