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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

bilayer creates is dynamic and interactive, becoming the foundation for many interactions involved in GPCR Read the complete article here: https://www.ecosystem.drgpcr.com/gpcr-binders-drugs-and-more/in-depth-molecular-profiling-of-an-intronic-gnao1 -mutant-as-the-basis-for-personalized-high-throughput-drug-screening References Grimes, J., Koszegi, Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics. Molecular mechanism of GPCR-mediated arrestin activation.

Loop 2 of the β 2-Adrenergic Receptor Coordinates β-Arrestin Interaction G protein-coupled receptors (GPCRs These receptors are the most clinically productive drug targets at present. The β2-adrenergic receptor (β2AR) is a prototypical and extensively studied GPCR that can provide insight into this aspect of GPCR signaling thanks to robust structural data and rich pharmacopeia. regulation that may contribute to biased signaling at GPCRs.

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Engineered G protein-coupled receptors (GPCRs) are commonly used in chemogenetics as designer receptors exclusively activated by designer drugs (DREADDs). Although several GPCRs have been studied in astrocytes using a chemogenetic approach, the functional

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Neuropeptides and their specific receptors (primarily G protein-coupled receptors, GPCRs) regulate multiple A total of 41 neuropeptide GPCR genes belonging to three classes were also identified. These GPCRs and their probable ligands were predicted. expression patterns of these 98 genes in various larval tissues were evaluated using quantitative real-time PCR to determine physiological functions and pharmacological characterization of neuropeptides and their GPCRs

Nanobody binding stabilizes G-protein-coupled receptors (GPCR) in a fully active state and modulates Altogether, our results provide insights into the effect of intracellular binding partners on the GPCR activation mechanism, which should be taken into account in structure-based drug discovery.

all cytomegalovirus (CMV) genomes analysed to date is the presence of G protein-coupled receptors (GPCR IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" which regulate All cytomegalovirus (CMV) genomes analysed to date possess GPCR homologs with phylogenetic evidence for The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and The signalling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance

It’s about finding purpose through loss, choosing academia when many peers walk away, and designing science street-level data shapes everything: dosing strategies that reflect actual potencies in seized samples, drug combinations that mirror contamination patterns, and experimental designs that evolve with new adulterants And GPCR pharmacology isn’t just an academic pursuit—it’s essential to understanding and responding to

Unexpectedly, Class A G protein-coupled receptors (GPCRs), a large class of signaling proteins exemplified transbilayer lipid movement, conceptualized as the swiping of a credit card (lipid) through a card reader (GPCR Conformational changes that facilitate scrambling are distinct from those associated with GPCR signaling In this review, we discuss the physiological significance of GPCR scramblase activity and the modes of

What if one simple graph could reveal the true power of a drug? From assessing drug potency to predicting effects, these curves aren't just for data—they’re your entry point to understanding drug behavior at a deeper level. real insight You'll leave with practical tools and a new appreciation for the humble curve that powers drug

Ever wondered why a drug behaves like a miracle in one tissue and a dud in another? foundational pharmacology is demystified by someone who’s spent over 40 years navigating the complexity of drug In his newest lesson, “The Uniqueness of Pharmacology in Drug Discovery,” Terry Kenakin explains why You’ll uncover: Why pharmacology is the glue between chemistry and biology How to interpret drug behavior

this study was to identify Gα proteins mediating function of neuronal G protein-coupled receptors (GPCRs Some neuronal GPCRs (such as GTR-1, DCAR-1, DOP-2, NPR-8, NPR-12, NPR-9, and DAF-37) functioned upstream of GOA-1, some neuronal GPCRs (such as DCAR-1, DOP-2, NPR-9, NPR-8, and DAF-37) functioned upstream of GSA-1, and some neuronal GPCRs (such as DOP-2, NPR-8, DAF-37, and DCAR-1) functioned upstream of GPA Our results provide clues for understanding the important function of GPCRs-Gα signaling cascade in the

Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs

molecular recognition of two peptidyl mating pheromones by their corresponding G-protein coupled receptors (GPCRs Here, we investigated the stringency of the two GPCRs, Mam2 and Map3, for their respective pheromones First, we switched GPCRs between S. pombe and the closely related species Schizosaccharomyces octosporus Thus, the differences in these two GPCRs might reflect the significantly distinct stringency/flexibility

The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 The recognition that GPCRs may physically interact with each other has led to the hypothesis that their Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing

And potential drug candidates left behind. From oxymetazoline to oxotremorine, discover how drugs can show up as full agonists in one system and If you're an emerging drug hunter, this lesson is your bridge from data confusion to predictive clarity

regulate a wide range of signaling events, most notably when bound to active G protein-coupled receptors (GPCRs Among the known effectors recruited by GPCR-bound arrestins are Src family kinases, which regulate cellular determined the crystal structure of the Fgr SH3 domain at 1.9 Å resolution and developed a model for the GPCR-arrestin

According with the National Institute on Drug Abuse (NIDA) nearly 92, 000 Americans died from drug-involved Opioids are analgesic drugs consumed non-medically for euphoric feelings and medically for pain relief Opioid receptors belong to class A of G protein-coupled receptors or GPCRs and signaled mainly through

vasoconstrictors, resulting in enhanced signalling through their cognate G protein-coupled receptors (GPCR Prolonged vasoconstrictor GPCR signalling increases arterial contraction and stimulates signalling pathways GPCR signalling through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) promotes VSMC proliferation In VSMC, G protein-coupled receptor kinase 2 (GRK2) is known to regulate numerous vasoconstrictor GPCRs

Sjögren's syndrome The etiology of primary Sjögren's syndrome (pSS) remains unknown, and there is no ideal drug is a key protein that mediates desensitization and internalization of G protein-coupled receptors (GPCRs

Alterations in the expression and/or activity of brain G-protein-coupled receptors (GPCRs) such as dopamine Since studies have indicated that flavonoids can target brain GPCRs and provide neuroprotection via inhibition Functional GPCR assays unfolded the compound's antagonist behavior on D1R (IC50 42.1 ± 0.35 μM) and agonist

Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR

SEPTEMBER 26-29, 2022 (Leipzig, Germany)​ 4GPCRnet meeting bringing together four of the biggest GPCR Four of the biggest European networks on GPCR research (COST Actions Adher’n Rise and ERNEST plus DFG-funded

Mutations in G protein-coupled receptors (GPCRs) underlie numerous diseases. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the These findings aid in advancing the understanding of the effects of genetic mutations on GPCR function

multiple immune signaling processes and is dependent on activation by Ras and G protein-coupled receptors (GPCRs that stimulated lipid kinase activity, block Ras activation, and specifically inhibited p101-mediated GPCR

foundational lesson, Terry Kenakin dives deep into a widely used, often misunderstood tool in early drug transient—giving rise to a “hemi-equilibrium” window that can significantly distort your understanding of drug

Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR

target for control of the fall webworm Hyphantria cunea Background: Insect G protein-coupled receptors (GPCRs HLGR2 is a typical GPCR and shows high structural and sequence similarity with other insect LGR2 proteins