September 2022 "The G-protein-coupled bile acid receptor, Gpbar1 or TGR5, is characterized as a membrane receptor specifically activated by bile acids. effects in different cancer cells upon activating via TGR5 agonists, such as INT-777, ursodeoxycholic acid (UDCA), and taurolithocholic acid (TLCA).

Lysophosphatidic acids (LPAs) are bioactive phospholipids implicated in a wide range of cellular activities

potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108.

Lysophosphatidic Acid and Several Neurotransmitters Converge on Rho-Kinase 2 Signaling to Manage Motoneuron MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism

October 2022 Recurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat "Introduction: Recurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. Objective: To study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. Methods: Using a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 Luciferase-based GloSensor™ cAMP assay: Temperature optimization and application to cell-based In this regard, luminescence-based biosensors have revolutionized our ability to monitor GPCR signaling

inflammation via enhancing NLRP3 inflammasome activation in macrophages "The putative medium-chain free fatty acid

One of the significant advantages of FRET and BRET-based sensors is their ability to provide real-time In conclusion, FRET and BRET-based sensors have transformed the landscape of GPCR research, offering As technology continues to advance, leveraging RET-based sensors will undoubtedly continue to propel Zhou, Y., et al., Multiple GPCR Functional Assays Based on Resonance Energy Transfer Sensors. 

August 2022 "The common mechanisms by which members of the G protein-coupled receptor (GPCR) family respond to neurotransmitters in the brain have been well studied. However, it is becoming increasingly clear that GPCRs show great diversity in their intracellular location, interacting partners and effectors, and signaling consequences. Here we will discuss recent studies on the diversity of location, effectors, and signaling of GPCRs, and how these could interact to generate specific spatiotemporal patterns of GPCR signaling in cells." Read more at the source #DrGPCR #GPCR #IndustryNews

Many such biosensors are based on the principle of Förster resonance energy transfer (FRET), and we have recently developed a simple approach for in vivo detection of FRET-based biosensor signals using fiber By combining fiber photometry with FRET-based biosensors, we were able to track GPCR-dependent signaling uses adeno-associated viruses infused intracerebrally in order to express genetically-encoded FRET-based

Here we developed and validated a label-free, liquid chromatography-mass spectrometry (LC-MS) based cell This assay was applied to various target classes, with particular emphasis on those for which protein-based

November 2022 "Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. The mGlu5 receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu5 receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu5 receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment- (1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu5 identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 μM, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling in functional assays. The results demonstrate that virtual screens of fragment- and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

Joe Clayton from BioTek Instruments talk about automated micro-plate-based methods for quantifying #GPCR

October 2022 "Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. The mGlu5 receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu5 receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu5 receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment- (1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu5 identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 μM, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling in functional assays. The results demonstrate that virtual screens of fragment- and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 A NanoBRET-Based H 3 R Conformational Biosensor to Study Real-Time H 3 Receptor Pharmacology We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor

Human-associated bacteria encode a variety of bioactive small molecules with growing evidence for N-acyl amides an N-acyltransferase encoded in the obligate human pathogen N. meningitidis and identified 30 N-acyl amides During this process, we also characterized two mammalian N-acyl amides derived from the bovine medium

April 2022 Trevena Receives up to $40M in OLINVYK ex-US Royalty-Based Financing from R-Bridge Healthcare with central nervous system (CNS) disorders, today announced that the Company entered into a royalty-based

bioinformatics are powerful tools to build modular, reproducible, and reusable pipelines for computer-aided

sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based

August 2022 "The cannabinoid CB1 receptor is the most abundant G protein coupled receptor (GPCR) in the central nervous system, which mediates the functional response to endocannabinoids and Cannabis compounds. A variety of ligands for CB1 receptors have been developed as promising drug candidates for the treatment of neurological disorders. New high-resolution structures of CB1 receptor in different functional states have significantly improved our molecular understanding of CB1 ligand interactions, selectivity, receptor activation and allosteric modulation. These advances have paved the way for development of novel ligands for different therapeutic applications. In this review, we describe the structural determinants for modulation of CB1 receptors by different types of ligands, as well as the differences between CB1 and its homologous, the CB2 receptor. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). " Read more at the source #DrGPCR #GPCR #IndustryNews

of G-protein-coupled receptors "Neural network (NN)-based protein modeling methods have improved significantly Although the overall accuracy of the two non-homology-based modeling methods, AlphaFold and RoseTTAFold This work directly compares the performance of these novel deep learning-based protein modeling methods for GPCRs with the most widely used template-based software-Modeller. The larger RMSD values generated by the NN-based methods were primarily due to the differences in loop

insights, together with the plethora of GPCR structures available today, will facilitate structure-based addition, we summarize current strategies for the identification of allosteric sites as well as ligand-based and structure-based drug discovery and design."

cryo-EM have resulted in a wealth of GPCR structures that have been used in drug design and formed the basis

October 2022 Case Report of a Juvenile Patient with Autism Spectrum Disorder with a Novel Combination Using array-based comparative genomic hybridization (array-CGH), we identified two CNVs, both triplex

August 2022 "Despite the importance of members of the GPCR superfamily as targets of a broad range of effective medicines many GPCRs remain poorly characterised. GPR84 is an example. Expression of GPR84 is strongly up regulated in immune cells in a range of pro-inflammatory settings and clinical trials to treat idiopathic pulmonary fibrosis are currently ongoing using ligands with differing levels of selectivity and affinity as GPR84 antagonists. Although blockade of GPR84 may potentially prove effective also in diseases associated with inflammation of the lower gut there is emerging interest in defining if agonists of GPR84 might find utility in conditions in which regulation of metabolism or energy sensing is compromised. Here, we consider the physiological and pathological expression profile of GPR84 and, in the absence of direct structural information, recent developments and use of GPR84 pharmacological tool compounds to study its broader role and biology. " Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying mutations vary considerably. In this work, we utilize deep mutational scanning to quantitatively compare the plasma membrane expression of 123 known pathogenic rhodopsin variants in the presence and absence of the stabilizing cofactor 9-cis-retinal. We identify 69 retinopathy variants, including 20 previously uncharacterized variants, that exhibit diminished plasma membrane expression in HEK293T cells. Of these apparent class II variants, 67 exhibit a measurable increase in expression in the presence of 9-cis-retinal. However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations. Evaluation of the observed shifts relative to thermodynamic estimates for the coupling between binding and folding suggests underlying differences in stability constrains the magnitude of their response to retinal. Nevertheless, estimates from computational modeling suggest that many of the least sensitive variants also directly compromise binding. Finally, we evaluate the functional properties of three previous uncharacterized, retinal-sensitive variants (ΔN73, S131P, and R135G) and show that two of these retain residual function in vitro. Together, our results provide a comprehensive experimental characterization of the proteostatic properties of retinopathy variants and their response to retinal." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

October 2022 Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case

structures of GPCRs bound to these interaction partners available today do not reveal a clear conformational basis