September 2022 Expression pattern and clinical significance of beta 2-adrenergic receptor in oral squamous cell However, the role of β2-AR in oral cancer is not well identified. significance in relation with the clinicopathological features and overall survival of oral squamous cell

protein signalling using a G protein activation assay and second messenger assay conducted on living cells

September 2022 A2B Adenosine Receptor Enhances Chemoresistance of Glioblastoma Stem-Like Cells under subpopulation that persists under hypoxic niches, called glioblastoma stem-like cells (GSCs). Transcript and protein levels were determined by RT-qPCR and Western blot, respectively. Cell viability was measured by MTS assays. Cell cycle and apoptosis were determined by flow cytometry.

Many cause receptor misfolding and failure to reach the cell surface. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the endoplasmic reticulum, stabilizing folding and "rescuing" cell surface expression. We previously demonstrated rescue of cell surface expression of luteinizing hormone receptor mutants of certain mutant FSHRs with severely reduced cell surface expression.

September 2022 Signaling pathways activated by sea bass gonadotropin-inhibitory hormone peptides in COS-7 cells on basal CRE-luc activity, they significantly decreased forskolin-elicited CRE-luc activity in COS-7 cells Moreover, an evident increase in SRE-luc activity was noticed when COS-7 cells expressing GnIHR were Notably, GnIH2 antagonized Kiss2-evoked CRE-luc activity in COS-7 cells expressing GnIHR and Kiss2 receptor and represent a starting point for the study of interactions with multiple neuroendocrine factors on cell

October 2022 Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein In this study, we generated and characterized human embryonic kidney 293A (HEK293A) cell lines devoid Additionally, using the Gαq/11 inhibitor YM-254890, GPCR kinase 2 and 3 (GRK2 and GRK3) KO cells, and Our PKC KO cell lines expand the repertoire of KO HEK293A cell lines available to research GPCR pharmacology lines as more specific research tools to investigate PKC-mediated aspects of cell biology."

Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis

August 2022 G protein-coupled receptor kinase type 2 and β-arrestin2: Key players in immune cell functions β-arrestin2 are key integrated signaling nodes in various biological processes, and both of them regulate cell proliferation and promote cell invasion and migration. This review summarizes the roles of GRK2/β-arrestin2 in immune cell function and focuses on the pathological

possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells.

PLC-IP3-ORAI pathway participates in the activation of the MRGPRB2 receptor in mouse peritoneal mast cells "A novel mast cell-specific G-protein-coupled receptor (GPCR), known as Mas-related G protein-coupled indicated the involvement of the PLC-IP3-ORAI signaling pathway and CACCS in MRGPRB2-mediated mast cell

Coordinated transcriptomics and peptidomics of central nervous system identify neuropeptides and their Here, we generated a transcriptome of the central nervous system (CNS) of G. molesta.

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various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal stem cells Application of mesenchymal stem cells (MSCs) as an emerging approach was recruited forthe treatment of Chemokines are low molecular weight proteins that their functional activities are achieved by binding to the cell Chemokine/chemokine receptor axes play a pivotal role in the recruitment and oriented trafficking of immune cells of MS patients via expression of various chemokine receptors in response to chemokines expressed by cells

Through gene expression analysis in immune and gastrointestinal cells, we show that these isoforms emerge Additionally, we employed optical assays in living cells to thoroughly profile both GPR35 isoforms for

GPR125 (ADGRA3), an orphan adhesion GPCR, has been shown to modulate planar cell polarity in gastrulating zebrafish, but its biochemical properties and role in mammalian cells have remained largely unknown. and human embryonic kidney HEK293 cells. Furthermore, in polarized MDCK cells, GPR125 is exclusively recruited to the basolateral domain of the in Matrigel 3D culture of MDCK cells.

Treatment of cells with YM failed to inhibit signaling by these PM-restricted αqQ209L.

Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R

Inhibition of autophagy by 3-methyladenine or interference of ATG5 or ATG7 attenuated HBx-induced cell dependent kinase 2; CDKN1B/p27Kip1: cyclin dependent kinase inhibitor 1B; CQ: chloroquine; E2F1: E2F transcription PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PHHs: primary human hepatocytes; RB1: RB transcriptional corepressor 1; SQSTM1/p62: sequestosome 1; STAT: signal transducer and activator of transcription; TACR1

October 2022 Glucagon receptor-mediated regulation of gluconeogenic gene transcription is endocytosis-dependent GPCRs) are now thought to use endocytosis to promote cellular cAMP signaling that drives downstream transcription epitope-tagged GCGRs undergo clathrin- and dynamin-dependent endocytosis in HEK293 and Huh-7-Lunet cells

September 2022 "The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte response to several different hypertrophic agents such as norepinephrine, angiotensin II and endothelin-1. PLC activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream signal transducers for the expression of fetal genes, increased protein synthesis, and subsequent cardiomyocyte growth. In this article, we describe the signal transduction elements that regulate PLC gene expression. The discussion is focused on the norepinephrine- α1-adrenoceptor signaling pathway and downstream signaling processes that mediate an upregulation of PLC isozyme gene expression. Evidence is also indicated to demonstrate that PLC activities self-regulate the expression of PLC isozymes with the suggestion that PLC activities may be part of a coordinated signaling process for the perpetuation of cardiac hypertrophy. Accordingly, from the information provided, it is plausible that specific PLC isozymes could be targeted for the mitigation of cardiac hypertrophy." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist-mediated activation mechanism "The mechanistic details of the tethered agonist mode of activation for the adhesion GPCR ADGRF5/GPR116 have not been completely deciphered. We set out to investigate the physiological importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro and in vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for function in vivo. Using site-directed mutagenesis and species-swapping approaches, we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane 7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Visual phototransduction is the most extensively studied G protein-coupled receptor (GPCR) signaling pathway because of its quantifiable stimulus, non-redundancy of genes, and immense importance in vision. We summarize recent discoveries that have advanced our understanding of rod outer segment (ROS) morphology and the pathological basis of retinal diseases. We have combined recently published cryo-electron tomography (cryo-ET) data on the ROS with structural knowledge on individual proteins to define the precise spatial limitations under which phototransduction occurs. Although hypothetical, the reconstruction of the rod phototransduction system highlights the potential roles of phosphodiesterase 6 (PDE6) and guanylate cyclases (GCs) in maintaining the spacing between ROS discs, suggesting a plausible mechanism by which intrinsic optical signals are generated in the retina." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Dimerization of β2-adrenergic receptor is responsible for the constitutive activity subjected to inverse agonism "Dimerization of beta 2-adrenergic receptor (β2-AR) has been observed across various physiologies. However, the function of dimeric β2-AR is still elusive. Here, we revealed that dimerization of β2-AR is responsible for the constitutive activity of β2-AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient β2-AR dimers exist in a resting state, and the dimer was disrupted by the inverse agonists. A Gαs preferentially interacts with dimeric β2-AR, but not monomeric β2-AR, in a resting state, resulting in the production of a resting cAMP level. The formation of β2-AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric β2-AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of β2-AR. Our model not only shows the function of dimeric β2-AR but also provides a molecular insight into the mechanism of the inverse agonism of β2-AR." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter

the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well

September 2022 "The follicle-stimulating hormone receptor (FSHR) belongs to the glycoprotein hormone receptors, a subfamily of G-protein-coupled receptors (GPCRs). FSHR is involved in reproductive processes such as gonadal development and maturation. Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question. We combined in vitro and in situ chemical crosslinking, disulfide pattern analysis, and mutation data with molecular modeling to generate experimentally driven full-length models. These models provide insights into the interface, important side-chain interactions, and activation mechanism. The interface indicates a strong involvement of the connecting loop. A major rearrangement of the HR seems implausible due to the tight arrangement and fixation by disulfide bonds. The models are expected to allow for testable hypotheses about signal transduction and drug development for GPHRs." Read more at the source #DrGPCR #GPCR #IndustryNews

Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor CXCR4 WHIM syndrome is a rare immunodeficiency disorder that is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. Here, we report on a new WHIM syndrome mutation that results in a frame shift within the codon for Ser339 (S339fs5) and compare the properties of S339fs5 with wild type CXCR4 and a previously identified WHIM syndrome mutant, R334X. The S339fs5 and R334X mutants exhibited significantly increased signaling compared to wild type CXCR4 including agonist-promoted calcium flux and extracellular signal-regulated kinase activation. This increase is at least partially due to a significant decrease in agonist-promoted phosphorylation, β-arrestin binding, and endocytosis of S339fs5 and R334X compared to wild type CXCR4. Interestingly, there were also significant differences in receptor degradation, with S339fs5 having a very high basal level of degradation compared to that of R334X and wild type CXCR4. In contrast to wild type CXCR4, both R334X and S339fs5 were largely insensitive to CXCL12-promoted degradation. Moreover, while basal and agonist-promoted degradation of wild type CXCR4 was effectively inhibited by the CXCR4 antagonist TE-14016, this had no effect on the degradation of the WHIM mutants. Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced signaling, reduced phosphorylation, β-arrestin binding and endocytosis, and a very high basal rate of degradation that is not protected by antagonist treatment. Read full article

A role for BET proteins in regulating basal, dopamine-induced and cAMP/PKA-dependent transcription in Upon activation via D1R, PKA can translocate to the nucleus to regulate transcription through the phosphorylation One candidate effector of PKA-dependent transcriptional regulation is the BET protein Brd4. it binds more readily to acetylated histones at promoters and enhancers; moreover, in non-neuronal cells However, it is unknown whether BET proteins, or Brd4 specifically, are involved in transcriptional activation

Congratulations to the GPCR Therapeutics team for their publication on improving hematopoietic stem cell pathways to regulate pancreatic β cell function GPCR Binders, Drugs, and more GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol Discovery GPCRs in Oncology and Immunology Comparative Analysis of the GNAI Family Genes in Glioblastoma through Transcriptomics and Single-Cell Technologies Methods & Updates in GPCR Research ThermoBRET: A Ligand-Engagement Nanoscale