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"Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction. We uncovered a novel neuroprotective mechanism involving interaction between neurotrophic factor-α1 (NF-α1/carboxypeptidase E, CPE) and human 5-HTR1E, a G protein-coupled serotonin receptor with no previously known neurological function. Co-immunoprecipitation and pull-down assays confirmed interaction between NFα1/CPE and 5-HTR1E and 125I NF-α1/CPE-binding studies demonstrated saturable, high-affinity binding to 5-HTR1E in stably transfected HEK293 cells (Kd = 13.82 nM). Treatment of 5-HTR1E stable cells with NF-α1/CPE increased pERK 1/2 and pCREB levels which prevented a decrease in pro-survival protein, BCL2, during H2O2-induced oxidative stress. Cell survival assay in β-arrestin Knockout HEK293 cells showed that the NF-α1/CPE-5-HTR1E-mediated protection against oxidative stress was β-arrestin-dependent. Molecular dynamics studies revealed that NF-α1/CPE interacts with 5-HTR1E via 3 salt bridges, stabilized by several hydrogen bonds, independent of the serotonin pocket. Furthermore, after phosphorylating the C-terminal tail and intracellular loop 3 (ICL3) of NF-α1/CPE-5-HTR1E, it recruited β-arrestin1 by forming numerous salt bridges and hydrogen bonds to ICL2 and ICL3, leading to activation of β-arrestin1. Immunofluorescence studies showed 5-HTR1E and NF-α1/CPE are highly expressed and co-localized on cell surface of human hippocampal neurons. Importantly, knock-down of 5-HTR1E in human primary neurons diminished the NF-α1/CPE-mediated protection of these neurons against oxidative stress and glutamate neurotoxicity-induced cell death. Thus, NF-α1/CPE uniquely interacts with serotonin receptor 5-HTR1E to activate the β-arrestin/ERK/CREB/BCL2 pathway to mediate stress-induced neuroprotection." Read full article

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essential for pipeline efficiency: How fast a ligand binds (k₁) and how long it stays bound (k₂)  can alter therapeutic When does onset rate dictate therapeutic onset, and when does offset rate predict duration? s Corner   ______ #DrugDiscovery #Pharmacology #DrugKinetics #PipelineEfficiency #PharmaInnovation #GPCR

GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types

accelerate and improve the prediction of first-in-class small molecule agonists for a challenging orphan GPCR for a highly relevant therapeutic need. 💊 InterAx Biotech AG discovery platform was already successfully #ai #biotech #systemsbiology #drugdiscovery #gpcr #deeptech #orphandrugs #pharma #partnerships #AI4drugdiscovery " Read more at the source #DrGPCR #GPCR #IndustryNews

That choice determines whether you risk over- or under-dosing, miss safety windows, or miss therapeutic Kenakin walks through this as a living system , showing how GPCRs exist in multiple conformations and More nuanced control, fewer off-target liabilities, and novel therapeutic windows. Correctly distinguishing these mechanisms helps refine therapeutic index calculations, prioritize safer GPCR members save  50%+  (check your Weekly News code).

Despite its therapeutic potential, CB2 pharmacology remains difficult to interrogate with confidence. chemistry decisions Why Live-cell High-Content Screening Matters for CB2 Ligand Profiling CB2 is a GPCR For GPCR programs—where trafficking, receptor reserve, and internalization are common confounders—access For researchers working in cannabinoid pharmacology, inflammation, or GPCR-mediated analgesia, these

protein-coupled receptor expression: Implications for metabolic regulation G protein-coupled receptors (GPCRs their secretion of insulin, and islet function can be modified by ligands acting at the large number of GPCRs is altered under pathophysiological conditions and, in this review, we have compared expression of GPCR We have also considered the likely outcomes on islet function that the altered GPCR expression status confers and the possible impact that adipokines, secreted from expanded fat depots, could have at those GPCRs

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In this sense, G protein-coupled receptors (GPCRs) may be a good option to try to prolong our life while substantial participation in a wide variety of processes of human pathophysiology and are one of the main therapeutic In this way, we present the analysis of a series of GPCRs whose activity has been shown to affect the Our compilation of data revealed that the mechanisms most involved in the role of GPCRs in lifespan are possibility of using agonist or antagonist drugs, depending on the beneficial or harmful effects of each GPCR

GPCR innovation is accelerating—those who act now will define tomorrow’s breakthroughs.

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GHSR1a The growth hormone secretagogue receptor 1a (GHSR1a) is intriguing because of its potential as a therapeutic Initial studies of the receptor focused on the potential therapeutic ability for growth hormone (GH) vitro and in vivo data suggest that GHSR1a heterodimerises with multiple G protein-coupled receptors (GPCRs This review discusses the signalling mechanisms of GHSR1a alone and in combination with other GPCRs, and explores the physiological consequences of GHSR1a coupling with other GPCRs.

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints

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structural positions in class A G protein-coupled receptors expressed in tumors G protein-coupled receptors (GPCRs Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs and potential approaches to therapeutics.

mechanosensation-dependent behavior in C. elegans via a trans function Latrophilins are highly conserved Adhesion GPCRs

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We also identified two Gs-coupled GPCRs that are endogenously expressed by SKM at relatively high levels

of the Inflammatory Cytokine IL-6 and Is Dependent on NF-κB Signaling G protein-coupled receptors (GPCRs Members of the Mas-related G protein coupled receptors (MRGPRs), a subfamily of GPCRs, are largely expressed

processes and serving as critical targets for therapeutic interventions. ' roles in immune function and potential therapeutic applications. abundant and rare GPCR transcripts. could be targeted to modulate inflammatory responses, offering potential therapeutic avenues for conditions the field continues to evolve, the insights gained from this research will be instrumental in shaping therapeutic

receptor-ligand complexes: Impact of ligand type and receptor activation state G protein-coupled receptors (GPCR Their abundance and role in nearly all physiological systems make GPCR the largest protein family targeted provided broadly generalizable performance expectations for docking into experimentally-characterized GPCR Simulations were performed using 37 experimental structures of 11 Class A GPCR crystallized in multiple Therefore, docking performance against GPCR targets can be estimated in advance based on docking target

the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic

Odorant G protein-coupled receptors as potential therapeutic targets for adult diffuse gliomas: a systematic and review Odorant receptors (ORs) account for about 60% of all human G protein-coupled receptors (GPCRs Glioma is the most common adult malignant brain tumor and requires novel therapeutic strategies to improve genomic and transcriptomic profiles of ORs in glioma, we suggest that ORs are potential biomarkers and therapeutic

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Ahoy, GPCR Crew! Receptors for New Therapeutic Options 📍  Boston, MA 📅 October 2 -3, 2024 Come and join top scientists INV-347 improves metabolic dysfunction in obese mice Aneesh Karatt Vellatt (CSO & Co-Founder, Maxion Therapeutics ) – BioLeader Interview Tectonic Therapeutic Announces Favorable Phase 1a Safety, Tolerability and PK Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and

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Ho, ho, ho, GPCR elves! GPCR ecosystem! Best, Yamina & the Dr. Don't miss out—upgrade now to keep up with your GPCR updates! Classified GPCR News  Let’s dive into the   Classified GPCR News from December 9th to 15th, 2024 Industry Jobs GPCR Molecular Pharmacologist Scientist - Biology Scientist I Cell Biology - Tectonic Therapeutic

This allows him to see how inflammation, cognition, and pain circuits overlap , and how GPCRs might serve as more responsive therapeutic nodes. And it challenges the GPCR community to use its tools not just to explain, but to intervene. the case for building pain research from the clinic down, not the bench up. ________ Keyword Cloud: GPCR podcast , pain modeling , GPCR online course , translational research , neuroimmune signaling .