September 2022 Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor

protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)-activating By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes

October 2022 "Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor (GPCR) activated by Once activated, PAR2 is rapidly desensitized and internalized by phosphorylation and β-arrestin recruitment Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been a bona fide agonist of PAR2 that induces unique cellular signaling, distinct from trypsin and PAR2-activating Activation of PAR2 by GB83 markedly elicited an increase in intracellular calcium levels and phosphorylation

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 Moreover, while basal and agonist-promoted degradation of wild type CXCR4 was effectively inhibited by Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced

Here, we revealed that dimerization of β2-AR is responsible for the constitutive activity of β2-AR generating The cholesterol did not interfere with the agonist-induced activation of monomeric β2-AR, unlike the

a wealth of GPCR structures that have been used in drug design and formed the basis for mechanistic activation

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

October 2022 Activation of GPR183 by 7 α,25-Dihydroxycholesterol Induces Behavioral Hypersensitivity through Mitogen-Activated Protein Kinase and Nuclear Factor- κ B "Emerging evidence implicates the G-protein tissues harvested at the time of peak hypersensitivity implicate potential contributions of mitogen-activated that the development of 7α,25-OHC/GPR183-induced mechano-allodynia was associated with significant activation insight into how GPR183 signaling in the spinal cord produces hypersensitivity through MAPK and NF-κB activation

September 2022 Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR "Background Fentanyl is an opioid analgesic and is widely used

September 2022 To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations "The δ-opioid receptor (DOR) is a critical In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism. in all three independent simulations, the receptor with ADL5859 was adopting toward the active conformation

These 5HT2C isoforms display differences in constitutive activity, agonist/inverse agonist potencies, To elucidate the molecular mechanisms responsible for these effects of RNA editing, we present four active-state We also provide a comprehensive analysis of agonist activation and constitutive activity across all 24 that is subject to RNA editing, which differentially affects GPCR constitutive and agonist signaling activities

However, the effects of the C tail- and TM core-mediated interactions on the conformational activation Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation , in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the C tail-mediated interactions together completely shift the equilibrium toward the activated conformation The conformation-selective antibody, Fab30, promotes partially activated βarr into the activated-like

typically necessary for G protein activation. between non-cognate G proteins and GPCRs, facilitating subsequent coupling of cognate G proteins and promoting prepare the GPCR in a manner that optimizes subsequent cognate G protein activation. cells lacking Gs proteins, a study by Stallaert et al. in 2017 showed that Gs played a pivotal role in calcium Overall, the increased calcium signalling was attributed to the release of ATP via β2AR-Gs mediated activation

A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling

physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate However, the detailed mechanism of aGPCR activation remains elusive. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. We further provide physiological evidence of GPR110 activation via stalk peptide.

August 2022 "Several G-protein coupled receptors (GPCR) are upregulated in Alzheimer's Disease (AD), which ought to facilitate neurotransmission, and improve cognition. Yet, despite this upregulation, associated physiological effects are not observed in AD patients. This paradox solicits urgent attention to find a suitable justification for disturbed neurotransmission in AD. This article focuses on the role of Aβ granules and their possible interaction with GPCRs that modulate neurotransmission and AD progression." Read more at the source #DrGPCR #GPCR #IndustryNews

targeting GPCRs focused on G-protein-dependent signaling pathways, such as those involving cAMP and calcium Extracellular signal-regulated kinases (ERK), a subset of the mitogen-activated protein kinase (MAPK) Initially, the activation of small GTPases like RAS leads to the activation of the MAP kinase kinase and activate ERK1 and ERK2. Minireview: targeting GPCR activated ERK pathways for drug discovery.

Here, we find that protease-activated receptor 4 (PAR4) unexpectedly acts as a potent oncogene, inducing β-catenin stability and transcriptional activity. residue at the N-terminal portion of β-catenin suppresses the ubiquitination of β-catenin, thereby promoting PAR-induced β-catenin stability and transcriptional activity. following PAR4 activation, in contrast to wt β-catenin.

Upon activation, GPCRs have conformational changes that allow the coupling and subsequent activation the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate of the G protein α subunit promoting the switch from activated to an inactivated state[3]. of the dopamine D2 receptor; enhancing the activity of the G protein that is coupled to the receptor to T cell activation[6].

Prokineticins (PKs) exert their biological functions through the activation of the G protein-coupled In the current report we present evidence of the modulation of PK2/PKR2 activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated kinase 1 The whey acidic protein domain (WAP) is necessary for this modulatory activity, although data from GST FnIII.1 domains could assist the WAP domain both in the binding to PKR2 and in the modulation of the activation

Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their The data support the inference that they act at the active interface between both transmembrane domains Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity

September 2022 Signaling pathways activated by sea bass gonadotropin-inhibitory hormone peptides in COS CRE-luc activity in COS-7 cells transfected with their cognate receptor GnIHR. Moreover, an evident increase in SRE-luc activity was noticed when COS-7 cells expressing GnIHR were However, GnIH peptides did not alter NFAT-RE-luc activity and ERK phosphorylation levels. Our results provide additional evidence for the understanding of signaling pathways activated by GnIH

February 2022 Read more at the source #DrGPCR #GPCR #IndustryNews

PI3Kγ is a critical component in multiple immune signaling processes and is dependent on activation by Ras and G protein-coupled receptors (GPCRs) to mediate its cellular roles. We identify nanobodies that stimulated lipid kinase activity, block Ras activation, and specifically inhibited p101-mediated GPCR activation.

Nanobody binding stabilizes G-protein-coupled receptors (GPCR) in a fully active state and modulates Here, we investigate the conformational changes induced by the binding of a nanobody (Nb80) on the active-like transmembrane helix 6 and a close proximity of transmembrane (TM) helices 5 and 7, and favors the fully active-like intracellular binding partner is bound, in which case the receptor is only stabilized in an intermediate-active This activation is supported by the residues located at hotspots located on TMs 5, 6, and 7, as shown

Objective: The goal of this study was to determine the glucometabolic effects of acute activation of relatively high levels (β2-adrenergic receptor and CRF2 receptor) and studied the acute metabolic effects of activating The acute metabolic effects following agonist activation of β2-adrenergic and, potentially, CRF2 receptors Conclusions: Selective activation of Gs signaling in SKM causes an acute increase in blood glucose levels

protein-coupled receptors (GPCRs) are commonly used in chemogenetics as designer receptors exclusively activated inhibits neuroinflammation, as characterized by decreased levels of proinflammatory cytokines, glial activation Similarly, in vitro calcium imaging showed that activation of the astrocytic Gi pathway attenuated intracellular calcium transients triggered by LPS treatment, suggesting a positive correlation between enhanced calcium

Constitutive, Basal, and β-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor along the Gαq/Phospholipase C (PLC) pathway, which results in an IkB kinases (IKK)-mediated canonical activation Additionally, we investigated the constitutive (ligand-independent) and basal activity of MRGPRD and concluded that the observed basal activity of MRGPRD is dependent on the presence of fetal bovine serum Consequently, the dynamic range for IL-6 detection as an assay for β-alanine-mediated activation of MRGPRD