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Celtarys Research Joins Dr. GPCR – Precision Tools for GPCR Assays Dr. GPCR and Celtarys Research have teamed up. Full Breakdown of the Latest in GPCR Research Want detailed insights? Dive into this week’s research, tools, and biotech updates all in one place.

This is Lucía from the Celtarys Research chemistry team.  For our very first post in this ecosystem, we wanted to highlight a huge part of our work at Celtarys Research

Thus, developing assays for commercially available probes such as CELT-419 would facilitate research For example, a Cy5-labelled fluorescent ligand with the same pharmacophore is available from Celtarys Research development of measurement methods can increase the quality and quantity of both fundamental receptor research

August 2022 TAS2R supports odontoblastic differentiation of human dental pulp stem cells in the inflammatory microenvironment "Background: Inflammatory microenvironment promotes odontoblastic differentiation in human dental pulp stem cells (hDPSCs), but the regulatory mechanisms remain unclear. In this study, we aimed to explore the role of TAS2R in odontoblastic differentiation of hDPSCs in the inflammatory microenvironment. Methods: Microarray analysis was performed to explore the differential mRNA profiles in inflammatory and healthy pulp tissues from the patients. hDPSCs isolated from the healthy pulp tissues were stimulated by LPS, TNFα and IL-6, respectively, to verify the effect of TAS2R. The expression markers related to odontoblastic differentiation of hDPSCs were observed by qPCR and chemical staining methods. TAS2R10 was overexpressed or silenced to observe the effect on odontoblastic differentiation of hDPSCs under LPS stimulation. The G protein and intracellular Ca2+ were detected, respectively, by qPCR and Fluo-4AM Ca2+ fluorescent probe." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 Exscientia and Sanofi Establish Strategic Research Collaboration to Develop AI-driven Pipeline capabilities and personalised medicine platform from target identification through patient selection Research will be focused on up to 15 novel small molecule candidates across oncology and immunology Exscientia royalties PARIS & OXFORD, England & BOSTON--Sanofi and Exscientia announced today a groundbreaking research novel bispecific small molecule candidate capable of targeting two distinct targets in inflammation and immunology

Despite their immense potential, utilizing FRET and BRET sensors in GPCR research comes with challenges In conclusion, FRET and BRET-based sensors have transformed the landscape of GPCR research, offering

December 2021 "Meet Peter McNamara, Ph.D., Tectonic’s SVP, Head of Research.

March 2022 ERNEST has established an Emergency Fund for Ukrainian researchers. "General Eligibility Researchers affiliated to any legal entity in Ukraine (for example, schools and universities, research centers, governmental institutions, or private companies) Deadlines Start of the who have been recently displaced by the war, or those who can travel to institutions participating in Our scientific perspective is broad, and we are happy to consider any research proposals from those in

Hello GPCR Trailblazers, This week, we’re spotlighting Celtarys Research, our newest partner, featured GPCR will help researchers move faster with custom fluorescent ligands, translational insight, and tool-enabled Introducing Celtarys - Probe Development via Conjugation Strategies   Celtarys Research's first article Constitutive ghrelin receptor activity, not dimerization or ligand binding —reverses dopamine D2 signaling Explore this week’s research, tools, and biotech insights in one place. The insights are ready.

Watch Episode 170 What We’re Missing in Pain Research In GPCR drug discovery, receptors typically steal where, as a mouse was starting to enter what we consider the chronic pain range, the mice that were constitutively against chronic pain. ___________ Keyword Cloud: RGS4 , GPCR data platform , GPCR training program , pain research

June 2022 "CRN04894 Selected for Oral Presentation SAN DIEGO, June 8, 2022 — Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), announced that results from the company’s Phase 1 study of CRN04894, the company’s investigational candidate for the treatment of Cushing’s disease, congenital adrenal hyperplasia (CAH) and other conditions driven by excess adrenocorticotropic hormone (ACTH), were selected for an oral presentation at ENDO 2022, the Endocrine Society’s annual meeting. Crinetics recently reported that administration of CRN04894 reduced both serum cortisol levels and 24-hour urine free cortisol excretion in the presence of sustained, disease-like ACTH concentrations in multiple-ascending dose cohorts of a Phase 1 study." Read more at the source #DrGPCR #GPCR #IndustryNews

Watch Episode 172 The Bigger Picture: GPCR Science Meets Public Health At its core, Catherine Demery’s research street-level contamination rising faster than medicine can adapt, Catherine’s work shows why overdose research Catherine’s research confronts this problem head-on by asking: What actually happens to breathing when From Street Samples to Lab Models What makes Catherine’s research particularly powerful is how it stays Without research that keeps pace, clinical tools will always be one step behind.

In the realm of molecular research, precise interpretation is crucial; a misread curve can lead to lost

August 2022 Addex and Indivior Extend GABAB Positive Allosteric Modulator Research Collaboration for US $900,000) of additional research funding.

October 2022 β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells "β-arrestins mediate regulatory processes for over 800 different G protein-coupled receptors (GPCRs) by adopting specific conformations that result from the geometry of the GPCR-β-arrestin complex. However, whether β-arrestin1 and 2 respond differently for binding to the same GPCR is still unknown. Employing GRK knockout cells and β-arrestins lacking the finger-loop-region, we show that the two isoforms prefer to associate with the active parathyroid hormone 1 receptor (PTH1R) in different complex configurations ("hanging" and "core"). Furthermore, the utilisation of advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when bound to active PTH1R (P-R*). Moreover, we assess β-arrestin conformational changes that are induced specifically by proximal and distal C-terminal phosphorylation and in the absence of GPCR kinases (GRKs) (R*). Here, we show differences between conformational changes that are induced by P-R* or R* receptor states and further disclose the impact of site-specific GPCR phosphorylation on arrestin-coupling and function." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter

October 2022 Cholesterol-Dependent Dynamics of the Serotonin1A Receptor Utilizing Single Particle Tracking: Analysis of Diffusion Modes "G protein-coupled receptors (GPCRs) are signaling hubs in cell membranes that regulate a wide range of physiological processes and are popular drug targets. Serotonin1A receptors are important members of the GPCR family and are implicated in neuropsychiatric disorders. Cholesterol is a key constituent of higher eukaryotic membranes and is believed to contribute to the segregated distribution of membrane constituents into domains. To explore the role of cholesterol in lateral dynamics of GPCRs, we utilized single particle tracking (SPT) to monitor diffusion of serotonin1A receptors under acute and chronic cholesterol-depleted conditions. Our results show that the short-term diffusion coefficient of the receptor decreases upon cholesterol depletion, irrespective of the method of cholesterol depletion. Analysis of SPT trajectories revealed that relative populations of receptors undergoing various modes of diffusion change upon cholesterol depletion. Notably, in cholesterol-depleted cells, we observed an increase in the confined population of the receptor accompanied by a reduction in diffusion coefficient for chronic cholesterol depletion. These results are supported by our recent work and present observations that show polymerization of G-actin in response to chronic cholesterol depletion. Taken together, our results bring out the interdependence of cholesterol and actin cytoskeleton in regulating diffusion of GPCRs in membranes." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics of ligands targeting G-protein-coupled receptors "Recently, academic and industrial scientific communities involved in kinetics-based drug development have become immensely interested in predicting the drug target residence time. Screening drug candidates in terms of their computationally predicted residence times, which is a measure of drug efficacy in vivo, and simultaneously assessing computational binding affinities are becoming inevitable. Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Here, we have implemented an optimized approach of combining the data derived from steered molecular dynamics simulations and the Bell-Evans model to predict the absolute residence times of the antagonist ZMA241385 and agonist NECA that target the A2A adenosine receptor of the G-protein-coupled receptor (GPCR) protein family. We have predicted the absolute ligand residence times on the timescale of seconds. However, our predictions were many folds shorter than those determined experimentally. Additionally, we calculated the thermodynamics of ligand binding in terms of ligand binding energies and the per-residue contribution of the receptor. Subsequently, binding pocket hotspot residues that would be important for further computational mutagenesis studies were identified. In the experiment, similar sets of residues were found to be in significant contact with both ligands under study. Our results build a strong foundation for further improvement of our approach by rationalizing the kinetics of ligand unbinding with the thermodynamics of ligand binding." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 Production of human A 2A AR in lipid nanodiscs for 19 F-NMR and single-molecule fluorescence spectroscopy "We describe production of the human A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule fluorescence (SMF) spectroscopy. We explain in detail steps shared between the two sample preparation strategies, including expression and isolation of A2AAR and assembly of A2AAR in lipid nanodiscs and procedures for incorporation of either 19F-NMR or fluorescence probes. Protocols for SMF experiments include sample setup, data acquisition, data processing, and error analysis. For complete details on the use and execution of this protocol, please refer to Wei et al. (2022) and Sušac et al. (2018)." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Background: Colorectal cancer is the third most common cancer and requires more prognostic The clinical significance of GPR39 in colon cancer has never been reported. Materials: In our study, we compared GPR39 expression between colon cancers and tumor-adjacent tissues by retrieving TCGA data and detected the expression of GPR39 in colon cancers with qPCR and immunohistochemistry

September 2022 Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation "Gut intraepithelial lymphocytes (IELs) are thought to calibrate glucagon-like peptide 1 (GLP-1) bioavailability, thereby regulating systemic glucose and lipid metabolism. Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP-1 secretion and glucose homeostasis nor for the metabolic benefits of GLP-1R agonists (GLP-1RAs). Instead, the gut IEL GLP-1R is essential for the full effects of GLP-1RAs on gut microbiota. Moreover, independent of glucose control or weight loss, the anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced, but not lipopolysaccharide-induced, inflammation. Such effects are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell receptor signaling in a protein-kinase-A-dependent manner. These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R activation in gut IELs to modulation of microbiota composition and control of intestinal and systemic inflammation." Read more at the source #DrGPCR #GPCR #IndustryNews

Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL-31, IL-4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas-related GPCRs and unexpected new pathways need to be also explored. Read full article

July 2022 Confo Therapeutics receives €1.7 million VLAIO grant for further research on GPCR modulators The grant should help expand Confo Therapeutic’s research on G protein-coupled receptor (GPCR) drug candidates

Career opportunities:  A curated list of new positions, including a Research Associate, a Senior Research Scientist, and a Post-doctoral Researcher position focused on GPCRs and Mitochondria. We’ve also highlighted the latest research on non-canonical internalization mechanisms of mGlu receptors the actionable intelligence you need to make sense of these trends and integrate them into your own research

September 2022 "Research on cancer therapies focuses on processes such as angiogenesis, cell signaling last decade, increasing evidence of its antitumoral properties in more than a dozen different types of cancer

September 2022 Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans "Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is

regulating proliferation, inflammation, adhesion, migration, insulin release, muscle relaxation, and cancer Several recent studies have demonstrated that TGR5 exerts inconsistent effects in different cancer cells

September 2022 High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes "Triple-negative breast cancer (TNBC) is a particularly aggressive It is generally considered that TNBC is an estrogen-independent breast cancer, while a new estrogen receptor

August 2022 A NanoBRET-Based H 3 R Conformational Biosensor to Study Real-Time H 3 Receptor Pharmacology in Cell Membranes and Living Cells "Conformational biosensors to monitor the activation state of G protein-coupled receptors are a useful addition to the molecular pharmacology assay toolbox to characterize ligand efficacy at the level of receptor proteins instead of downstream signaling. We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor (H3R) biosensor that allowed the detection of both (partial) agonism and inverse agonism on living cells in a microplate reader assay format upon stimulation with H3R ligands. In the current study, we have further characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time and evaluating its compatibility with photopharmacological ligands that contain a light-sensitive azobenzene moiety for photo-switching. In addition, we have validated the H3R biosensor in membrane preparations and found that observed potency values better correlated with binding affinity values that were measured in radioligand competition binding assays on membranes. Hence, the H3R conformational biosensor in membranes might be a ready-to-use, high-throughput alternative for radioligand binding assays that in addition can also detect ligand efficacies with comparable values as the intact cell assay." Read more at the source #DrGPCR #GPCR #IndustryNews

Hence, it has wide applicability across a spectrum of neuroscience research, ranging from the study of

September 2022 GASP1 enhances malignant phenotypes of breast cancer cells and decreases their response However, its biological function and underlying molecular mechanism in breast cancer have not been clearly Here, we demonstrated that GASP1 was highly expressed in breast cancers, and patients harboring altered Functional studies showed that GASP1 knockout significantly suppressed malignant properties of breast cancer Collectively, this study demonstrates that GASP1 enhances malignant behaviors of breast cancer cells