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October 2022 Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations "Allosteric modulators are called promising candidates in G protein-coupled receptor (GPCR) drug development by displaying subtype selectivity and more specific receptor modulation. Among the allosteric sites known to date, cavities at the receptor-lipid interface represent an uncharacteristic binding location that raises many questions about the ligand interactions and stability, the binding site structure, and how all of these are affected by lipid molecules. In this work, we analyze interactions in the allosteric sites of the PAR2, C5aR1, and GCGR receptors in three lipid compositions using molecular dynamics simulations. In addition, we performed quantum chemical calculations involving the symmetry-adapted perturbation theory (SAPT) and the natural population analysis to quantify the strength of intermolecular interactions. We show that besides classical hydrogen bonds, weak polar interactions such as O-HC, O-Br, and long-range electrostatics with the backbone amides contribute to the stability of allosteric modulators at the receptor-lipid interface. The allosteric cavities are detectable in various membrane compositions. The availability of polar atoms for interactions in such cavities can be assessed by water molecules from simulations. Although ligand-lipid interactions are weak, lipid tails play a role in ligand binding pose stability and the size of allosteric cavities. We discuss physicochemical aspects of ligand binding at the receptor-lipid interface and suggest a compound library enriched by weak donor groups for ligand search in such sites." Read more at the source #DrGPCR #GPCR #IndustryNews

. ✅ Insight into Consequences:  How binding sites determine receptor state shifts, signaling outcomes Orthosteric ligands preempt  natural signaling; they “take over” receptor behavior, forcing physiology , act more like tuning knobs—modulating receptor ensembles in partnership with the system’s ongoing signaling For drug discovery teams navigating safety margins, biased signaling, and combination therapy design, This means you can design molecules that potentiate beneficial pathways without shutting down basal signaling

relationship between the conformational change of the receptor because of the mutation and related downstream signaling understanding of the relationship between the changed conformation of the receptor and consequently activated signaling

We have previously reported that the MC4R forms homodimers, affecting receptor Gs signaling properties In this study, we analyzed effects of inhibiting homodimerization on Gq/11 signaling using previously Gq/11 signaling of chimeric receptors was analyzed using luciferase-based reporter gene (NFAT) assays Results demonstrate an improvement of alpha-MSH-induced NFAT signaling of chimeras, reaching the level of setmelanotide signaling at wild-type MC4R (MC4R-WT).

activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated

We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from

focus on the relatively less well-studied effects of GPCRs in cardiac fibroblasts, focusing on key signaling We also review the hierarchy of signaling events driving the fibrotic response and the communications We discuss how such events may be distinct depending on where the GPCRs and their associated signaling Finally, we explore what such connections between the cell surface and nuclear GPCR signaling might mean

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. together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced signaling

bias "Within the intestine, the human G protein-coupled receptor (GPCR) GPR35 is involved in oncogenic signaling cells to thoroughly profile both GPR35 isoforms for constitutive and ligand-induced activation and signaling

September 2022 "GPCR signaling and function depend on their associated proteins and subcellular locations they connect a large number of diverse proteins to form signaling networks. We found that some agonist-induced GPCR/14-3-3 signal intensities can rapidly decrease. could also be paralleled with GPCR/β-arrestin-2 signals, indicating diminished levels of GPCR/signal a new approach for GPCR drug development by modulating GPCR/14-3-3 signals temporally."

in the role of GPCRs in lifespan are those that mimic dietary restriction, those related to insulin signaling

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors "Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

papers—it demands access to the right frameworks and expert insights that separate the noise from the signal Breakthroughs this week: Glucagon-like Peptide-1 Receptor (GLP-1R) Signaling; Proximity-Dependent Proteomics Upcoming events:  Get details on the "neuroGPCR" symposium focusing on receptor signaling and a platform Expand your computational toolkit ➤ Call for Papers: GPCRs: Signal Transduction, Volume II Building on the success of its first volume, the research topic "GPCRs: Signal Transduction: Volume II" is now open

2022 "Heterotrimeric G proteins couple activated G protein-coupled receptors (GPCR) to intracellular signaling of GPCR activation upon acquiring mutations that prevent GTPase activity and result in constitutive signaling YM-254890 (YM) can inhibit signaling by both GPCR-activated wild type αq and GPCR-independent αqQ209L Treatment of cells with YM failed to inhibit signaling by these PM-restricted αqQ209L. GPCR-dependent signaling by PM-restricted wild type αq is strongly inhibited by YM, demonstrating that

activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream signal 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 the expression of PLC isozymes with the suggestion that PLC activities may be part of a coordinated signaling

monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses

7 pass transmembrane domain, Class F GPCR family protein) plays a crucial role in the Hedgehog (HH) signaling In the absence of HH signaling, SMO is inhibited by Patched 1 (PTC1; a 12 pass transmembrane domain protein

Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors The biased signaling modulation of non-GPCR receptors has yet to be exploited. receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates.

We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible

However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory Instead, fast calcium signals in PFC astrocytes are time locked to dopamine release and are mediated Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to

October 2022 "Enzymatic and cellular signalling biosensors are used to decipher the activities of complex selectivity, with an emphasis on sensors measuring receptor association and activation of heterotrimeric signalling

How this HR is involved in hormone binding and signal transduction is still an open question. The models are expected to allow for testable hypotheses about signal transduction and drug development

GPCR Activation and Signaling G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia Re-routing GPR56 signaling in Oncology and Immunology Chemokine Cxcl1-Cxcl2 heterodimer is a potent neutrophil chemoattractant Neuroimmune , 2023 | Training Seminar "The Renaissance in GPCRs as Drug Targets: Allosteric Function and Biased Signaling

Ca2+ (Ca2+o ) via a dimeric extracellular Venus flytrap (VFT) unit that activates G protein-dependent signaling corresponding to heterozygous familial hypocalciuric hypercalcemia type-1 (FHH-1), supported maximal signaling In contrast, a single WT HH bundle was insufficient for maximal signaling and there was no functional Finally, we observed that the Ca2+o -stimulated CaSR operated exclusively via signaling in-trans and not via combined in-trans and in-cis signaling.

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

August 2022 "The calcium-permeable cation channel TRPM3 can be activated by heat and the endogenous steroid pregnenolone sulfate. TRPM3's best understood function is its role as a peripheral noxious heat sensor in mice. However, the channel is expressed in various tissues and cell types including neurons as well as glial and epithelial cells. TRPM3 expression patterns differ between species and change during development. Furthermore, a plethora of TRPM3 variants that result from alternative splicing have been identified and the majority of these isoforms are yet to be characterized. Moreover, the mechanisms underlying regulation of TRPM3 are largely unexplored. In addition, a micro-RNA gene (miR-204) is located within the TRPM3 gene. This complexity makes it difficult to obtain a clear picture of TRPM3 characteristics. However, a clear picture is needed to unravel TRPM3's full potential as experimental tool, diagnostic marker and therapeutic target. Therefore, the newest data related to TRPM3 have to be discussed and to be put in context as soon as possible to be up-to-date and to accelerate the translation from bench to bedside. The aim of this review is to highlight recent results and developments with particular focus on findings from studies involving ocular tissues and cells or peripheral neurons of rodents and humans." Read more at the source #DrGPCR #GPCR #IndustryNews

This facilitates the study of receptor dynamics, ligand binding and signaling in real time. fluorescent tags to study biased signaling pathways, improving our understanding of GPCR functional Innovations in the fluorophore tags, such as pH sensitive probes, can further improve signal-to-noise The compatibility of fluorophore and detector is key to ensure a clean signal. Cell Commun Signal. 2009 Jul 14;7:16. doi: 10.1186/1478-811X-7-16  Siddiqui S, Livák F.

GPCRs play a central role in neuronal signaling and have been used to treat these diseases with varying GPCR Structure, Activation, and Signaling Pathways in the Brain An understanding of GPCR structure is GPCRs posses a seven-transmembrane domain architecture, which lets them transduce extracellular signals GPCR signaling: (A) an orthosteric ligand (orange) binds an inactive GPCR, the β2 adrenergic receptor Reduced background noise: Improvements in signal-to-noise ratio are key in CNS assays.

While others pivoted, Sokhom went deeper: refining assays, exploring signaling bias, and building a robust Advances in biased signaling, allosterism, and endosomal signaling have opened new therapeutic frontiers