activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) pathway elicited by PK2 through PKR2.

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

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

extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway 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

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

2022 "Heterotrimeric G proteins couple activated G protein-coupled receptors (GPCR) to intracellular signaling pathways. 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.

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

pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. 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

September 2022 PLC-IP3-ORAI pathway participates in the activation of the MRGPRB2 receptor in mouse peritoneal Our results indicated the involvement of the PLC-IP3-ORAI signaling pathway and CACCS in MRGPRB2-mediated

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. pathways. 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.

September 2022 "Class A (rhodopsin-like) G protein-coupled receptors (GPCRs) are constitutive phospholipid scramblases as evinced after their reconstitution into liposomes. Yet phospholipid scrambling is not detectable in the resting plasma membrane of mammalian cells that is replete with GPCRs. We considered whether cholesterol, a prominent component of the plasma membrane, limits the ability of GPCRs to scramble lipids. Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded opsin indicated that phospholipid headgroups traverse a dynamically revealed hydrophilic groove between transmembrane helices (TM) 6 and 7 while their tails remain in the bilayer. Here, we present comparative MSM analyses of 150-μs simulations of opsin in cholesterol-free and cholesterol-rich membranes. Our analyses reveal that cholesterol inhibits phospholipid scrambling by occupying the TM6/7 interface and stabilizing the closed groove conformation while itself undergoing flip-flop. This mechanism may explain the inability of GPCRs to scramble lipids at the plasma membrane." Read more at the source #DrGPCR #GPCR #IndustryNews

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 find that PFC astrocytes express receptors for dopamine but are unresponsive through the Gs/Gi-cAMP pathway 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

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

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

been studied in astrocytes using a chemogenetic approach, the functional role of the astrocytic Gi pathway In this study, we evaluated the role of the astrocytic Gi pathway in neuroinflammation using a Gi -coupled Similarly, in vitro calcium imaging showed that activation of the astrocytic Gi pathway attenuated intracellular Taken together, our results indicate that the astrocytic Gi pathway plays an inhibitory role in neuroinflammation

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

September 2022 Endothelin-1 Stimulates PAI-1 Protein Expression via Dual Transactivation Pathway Dependent In addition, as an intermediary of G protein-coupled receptor (GPCR) signaling, the functions of ROCK and PLC were investigated in dual transactivation pathways. the phosphorylation of Smad2L and protein expression of PAI-1<br />via induced the transactivation pathways

September 2022 High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways Transcriptome-based bioinformatics analysis revealed that GPER was linked to pro-metastatic pathways

September 2022 "Background Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. Methods We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution." Read more at the source #DrGPCR #GPCR #IndustryNews

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

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.

., for their research on GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the in adhesion G protein-coupled receptors GPCR Activation and Signaling A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade Allatotropin (AT) related peptides neuroprotective and neurogenic properties GPCRs in Oncology and Immunology Chemoattractant receptor signaling

GPCR Activation and Signaling Single transmembrane GPCR modulating proteins: neither single nor simple CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA. A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants GPCRs in Oncology and Immunology The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways

GPCR Activation and Signaling Neuronal survival factor TAFA2 suppresses apoptosis through binding to ADGRL1 and activating cAMP/PKA/CREB/BCL2 signaling pathway Deciphering specificity and cross-reactivity model of polycystic ovarian syndrome by modulating GPCR41/43 and PROKR1 GPCRs in Neuroscience Diverse signaling Alzheimer's disease GPCRs in Oncology and Immunology Context-dependent ciliary regulation of hedgehog pathway Pharmaceuticals Announces November 2023 Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) GPCR 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

GPCR Activation and Signaling The G protein alpha chaperone and guanine-nucleotide exchange factor RIC regulates cilia morphogenesis in Caenorhabditis elegans sensory neurons CaSR links endocytic and secretory pathways pathway GPCR Binders, Drugs, and more Cloning and deorphanization of three inotocin (insect oxytocin Part II: Cell Cycle, DNA Damage Response, and Apoptosis Pathways Spliceosome mutations are associated Optical Approaches for Investigating Neuromodulation and G Protein-Coupled Receptor Signaling Protocol

pathway in zebrafish embryos. GPCRs in Neuroscience Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different GPCRs in Oncology and Immunology Dynamic Phosphoproteomics of BRS3 Activation Reveals the Hippo Signaling Pathway for Cell Migration. Autocrine proteinase-activated receptor signaling in PC3 prostate cancer cells.