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🌟The Dr. GPCR event of the year is the 3rd edition of the Summit. Come join us from October 10 to 16 to hear about exciting #GPCR research from amazing speakers. Become a Dr. GPCR Ecosystem site member to attend the Summit, it’s free! ➡️ https://bit.ly/3SUkB8D #gpcr #drgpcr

September 2022 Signaling pathways activated by sea bass gonadotropin-inhibitory hormone peptides in COS-7 cells transfected with their cognate receptor "Results of previous studies provided evidence for the existence of a functional gonadotropin-inhibitory hormone (GnIH) system in the European sea bass, Dicentrarchus labrax, which exerted an inhibitory action on the brain-pituitary-gonadal axis of this species. Herein, we further elucidated the intracellular signaling pathways mediating in sea bass GnIH actions and the potential interactions with sea bass kisspeptin (Kiss) signaling. Although GnIH1 and GnIH2 had no effect on basal CRE-luc activity, they significantly decreased forskolin-elicited 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 challenged with both GnIH peptides, and this stimulatory action was significantly reduced by two inhibitors of the PKC pathway. Notably, GnIH2 antagonized Kiss2-evoked CRE-luc activity in COS-7 cells expressing GnIHR and Kiss2 receptor (Kiss2R). However, GnIH peptides did not alter NFAT-RE-luc activity and ERK phosphorylation levels. These data indicate that sea bass GnIHR signals can be transduced through the PKA and PKC pathways, and GnIH can interfere with kisspeptin actions by reducing its signaling. Our results provide additional evidence for the understanding of signaling pathways activated by GnIH peptides in teleosts, and represent a starting point for the study of interactions with multiple neuroendocrine factors on cell signaling." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response "Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could alleviate DVT and its underlying mechanism has not been elucidated." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The complement fragment C5a is one of the most potent proinflammatory glycoproteins liberated by the activation of the biochemical cascade of the complement system. C5a is established to interact with a set of genomically related transmembrane receptors, like C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2) with comparable affinity. The C5aR1 is a classical G-protein-coupled receptor (GPCR), whereas C5aR2 is a nonclassical GPCR that tailors immune cell activity potentially through β-arrestins rather than G-proteins. Currently, the exact function of the C5aR2 is actively debated in the context of C5aR1, even though both C5aR1 and C5aR2 are coexpressed on myriads of tissues. The functional relevance of C5aR2 appears to be context-dependent compared to the C5aR1, which has received enormous attention for its role in both acute and chronic inflammatory diseases. In addition, the structure of C5aR2 and its interaction specificity toward C5a is not structurally elucidated in the literature so far. The current study has attempted to close the gap by generating highly refined model structures of C5aR2, respectively in free (inactive), complexed to C-terminal peptide of C5a (meta-active) and the C5a (active), embedded to a model palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer. The computational modeling and the 1.5-μs molecular dynamics data presented in the current study are expected to further enrich the understanding of C5a-C5aR2 interaction compared to C5a-C5aR1, which will surely help in elaborating the currently debated biological function of C5aR2 better in the foreseeable future." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Introduction Protease activated receptors 1 (PAR1) and 4 (PAR4) agonists are used to study platelet activation. Data on platelet activation are extrapolated across experimental settings. C1-inhibitor (C1INH) is a protease inhibitor present in plasma but not in isolated platelet suspensions. Here we show that C1INH affects platelet activation through PAR1 and PAR4 agonists. Methods Platelets were isolated from healthy donor whole blood and then labeled with anti-CD62P and PAC1 antibodies. The platelet suspensions were exposed to PAR1 agonists SFLLRN, TFLLR and TFLLRN; PAR4 agonists AYPGKF and GYPGQV; ADP and thrombin. Flow-cytometric measurements were performed in 5, 10 and 15 min after activation." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Background and purpose: The interaction of arrestins with G-protein coupled receptors (GPCRs) desensitizes agonist-dependent receptor responses and often leads to receptor internalization. GPCRs that internalize without arrestin have been classified as "class A" GPCRs whereas "class B" GPCRs co-internalize with arrestin into endosomes. The interaction of arrestins with GPCRs requires both agonist activation and receptor phosphorylation. Here, we ask the question whether agonists with very slow off-rates can cause the formation of particularly stable receptor-arrestin complexes." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis "Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Epithelial tube formation requires Rho1-dependent actomyosin contractility to generate the cellular forces that drive cell shape changes and rearrangement. Rho1 signaling is activated by G-protein-coupled receptor (GPCR) signaling at the cell surface. During Drosophila embryonic salivary gland (SG) invagination, the GPCR ligand Folded gastrulation (Fog) activates Rho1 signaling to drive apical constriction. The SG receptor that transduces the Fog signal into Rho1-dependent myosin activation has not been identified. Here, we reveal that the Smog GPCR transduces Fog signal to regulate Rho kinase accumulation and myosin activation in the medioapical region of cells to control apical constriction during SG invagination. We also report on unexpected Fog-independent roles for Smog in maintaining epithelial integrity and organizing cortical actin. Our data support a model wherein Smog regulates distinct myosin pools and actin cytoskeleton in a ligand-dependent manner during epithelial tube formation." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Evaluation of stimulus salience is critical for any higher organism, as it allows for prioritizing of vital information, preparation of responses, and formation of valuable memory. The paraventricular nucleus of the thalamus (PVT) has recently been identified as an integrator of stimulus salience but the neurochemical basis and afferent input regarding salience signaling have remained elusive. Here we report that neuropeptide S (NPS) signaling in the PVT is necessary for stimulus salience encoding, including aversive, neutral and reinforcing sensory input. Taking advantage of a striking deficit of both NPS receptor (NPSR1) and NPS precursor knockout mice in fear extinction or novel object memory formation, we demonstrate that intra-PVT injections of NPS can rescue the phenotype in NPS precursor knockout mice by increasing the salience of otherwise low-intensity stimuli, while intra-PVT injections of NPSR1 antagonist in wild type mice partially replicates the knockout phenotype. The PVT appears to provide stimulus salience encoding in a dose- and NPS-dependent manner. PVT NPSR1 neurons recruit the nucleus accumbens shell and structures in the prefrontal cortex and amygdala, which were previously linked to the brain salience network. Overall, these results demonstrate that stimulus salience encoding is critically associated with NPS activity in the PVT." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Endothelin-1 Stimulates PAI-1 Protein Expression via Dual Transactivation Pathway Dependent ROCK and Phosphorylation of Smad2L "In addition to the carboxy region, Smad2 transcription factor can be phosphorylated in the linker region aswell. Phosphorylation of Smad2 linker region (Smad2L) promotes the expression of plasminogen activator inhibitor type1 (PAI-1) which leads to cardiovascular disorders such as atherosclerosis. The purpose of this study was to evaluate the role of dual transactivation of EGF and TGF-β receptors in phosphorylation of Smad2L and protein expression of PAI-1 induced by endothelin-1 (ET-1) in bovine aortic endothelial cells (BAECs). In addition, as an intermediary of G protein-coupled receptor (GPCR) signaling, the functions of ROCK and PLC were investigated in dual transactivation pathways.Materials and Methods: The experimental study is an in vitro study performed on BAECs. Proteins were investigatedby western blotting using protein-specific antibodies against phospho-Smad2 linker region residues (Ser245/250/255),phospho-Smad2 carboxy residues (465/467), ERK1/(Thr202/Thr204), and PAI-1.Results: TGF (2 ng/ml), EGF (100 ng/ml) and ET-1 (100 nM) induced the phosphorylation of Smad2L. This response wasblocked in the presence of AG1478 (EGFR antagonists), SB431542 (TGFR inhibitor), and Y27632 (Rho-associated protein kinase (ROCK antagonist). Moreover, ET-1-increased protein expression of PAI-1 was decreased in the presence of bosentan (ET receptor inhibitor), AG1478, SB431542, and Y27632.Conclusion: The results indicated that ET-1 increases the phosphorylation of Smad2L and protein expression of PAI-1via induced the transactivation pathways of EGFR and TGFR. This study is the first attempt to scrutinize the significant role of ROCK in the protein expression of PAI-1." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Lack of Oestrogen Receptor Expression in Breast Cancer Cells Does Not Correlate with Kisspeptin Signalling and Migration "Kisspeptin is an anti-metastatic mediator in many cancer types, acting through its receptor, KISS1R. However, controversy remains regarding its role in breast cancer since both pro- and anti-metastatic roles have been ascribed to it. In KISS1R overexpressing triple-negative breast cancer (TNBC) cells, stimulation has been associated with increased invasion and MMP-9 expression, leading to the suggestion that hormone receptor status determines the metastatic effects of kisspeptin. To assess the veracity of this claim, we compared endogenous KISS1R signalling and physiological output in the hormone receptor-negative MDA-MB-231 and BT-20 cell lines after KP-10 (shortest active kisspeptin peptide) stimulation. MDA-MB-231 cells are metastatic when implanted in mice while BT-20 are not and remain epithelial-like. We show that both cell lines express KISS1R mRNA and respond to KP-10 by elevating calcium mobilisation. However, KP-10 stimulation induced migration of MDA-MB-231, but not BT-20 cells, in a calcium-dependent manner. Moreover, only BT-20 cells responded to KP-10 by increasing ERK phosphorylation in a β-arrestin-dependent manner. Interestingly, both cell lines displayed different complements of β-arrestin 1 and 2 expression. Overall, our data shows that, in TNBC, it is not universally true that kisspeptin/KISS1R stimulate migration or pro-metastatic behaviour, as divergent responses were observed in the two TNBC lines tested. Whether this divergence is related to the observed differences in β-arrestin complements warrants further investigation and may enable further stratification of the ability of kisspeptin to influence breast tumour behaviour." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The GPR15 receptor is a G protein-coupled receptor (GPCR), which is activated by an endogenous peptide GPR15L(25-81) and a C-terminal peptide fragment GPR15L(71-81). GPR15 signals through the Gi/o pathway to decrease intracellular cyclic adenosine 3',5'-monophosphate (cAMP). However, the activation profiles of the GPR15 receptor within Gi/o subtypes have not been examined. Moreover, whether the receptor can also couple to Gs , Gq/11 and G12/13 is unclear. Here, GPR15L(25-81) and GPR15L(71-81) are used as pharmacological tool compounds to delineate the GPR15 receptor-mediated Gα protein signalling using a G protein activation assay and second messenger assay conducted on living cells. The results show that the GPR15 receptor preferentially couples to Gi/o rather than other pathways in both assays. Within the Gi/o family, the GPR15 receptor activates all the subtypes (Gi1 , Gi2 , Gi3 , GoA , GoB and Gz ). The Emax and activation rates of Gi1, Gi2 , Gi3, GoA and GoB are similar, whilst the Emax of Gz is smaller and the activation rate is significantly slower. The potencies of both peptides toward each Gi/o subtype have been determined. Furthermore, the GPR15 receptor signals through Gi/o to inhibit cAMP accumulation, which could be blocked by the application of the Gi/o inhibitor pertussis toxin." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Regulator of G Protein Signaling 20 Correlates with Long Intergenic Non-Coding RNA (lincRNAs) Harboring Oncogenic Potential and Is Markedly Upregulated in Hepatocellular Carcinoma "Hepatocellular carcinoma (HCC) is at the forefront of the global cancer burden, and biomarkers for HCC are constantly being sought. Interestingly, RGS (Regulators of G protein signaling) proteins, which negatively regulate GPCR signaling, have been associated with various cancers, with some members of the RGS family being associated with liver cancer as well. Considering this, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancer types with special emphasis on HCC. By using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, our analysis revealed that (a) RGS20 was strongly upregulated in tumor tissue compared with adjacent normal tissue of HCC patients; (b) RGS20 was strongly associated with some important clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p < 0.001), RGS20 was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p < 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways and long intergenic non-coding RNAs (lincRNAs: LINC00511, PVT1, MIR4435-2HG, BCYRN1, and MAPKAPK5-AS1) that exhibit oncogenic potential. Taken together, we showed that RGS20 correlates with a few HCC-associated lincRNAs harboring oncogenic potential and is markedly upregulated in HCC patients. Our analysis further supports the putative function of RGS proteins, particularly RGS20, in cancer." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 Microbial Metabolites Orchestrate a Distinct Multi-Tiered Regulatory Network in the Intestinal Epithelium That Directs P-Glycoprotein Expression "P-glycoprotein (P-gp) is a key component of the intestinal epithelium playing a pivotal role in removal of toxins and efflux of endocannabinoids to prevent excessive inflammation and sustain homeostasis. Recent studies revealed butyrate and secondary bile acids, produced by the intestinal microbiome, potentiate the induction of functional P-gp expression. We now aim to determine the molecular mechanism by which this functional microbiome output regulates P-gp. RNA sequencing of intestinal epithelial cells responding to butyrate and secondary bile acids in combination discovered a unique transcriptional program involving multiple pathways that converge on P-gp induction. Using shRNA knockdown and CRISPR/Cas9 knockout cell lines, as well as mouse models, we confirmed the RNA sequencing findings and discovered a role for intestinal HNF4α in P-gp regulation. These findings shed light on a sophisticated signaling network directed by intestinal microbial metabolites that orchestrate P-gp expression and highlight unappreciated connections between multiple pathways linked to colonic health." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The diamondback moth (Plutella xylostella) is one of the most destructive lepidopteran pests of cruciferous vegetables, and insights into regulation of its physiological processes contribute towards the development of new pesticides against it. Thus, we investigated the regulatory functions of its β-adrenergic-like octopamine receptor (PxOctβ3). The open reading frame (ORF) of PxOctβ3 was phylogenetically analyzed, and the levels of expression of the receptor mRNA were determined. This ORF was also cloned and expressed in HEK-293 cells. A series of octopamine receptor agonists and antagonists were tested against PxOctβ3. We showed that the receptor is a member of the Octβ3 protein family, and an analysis using quantitative PCR showed that it was expressed at all developmental stages of P. xylostella. Octopamine activated PxOctβ3, resulting in increased levels of intracellular cAMP. Furthermore, the agonists naphazoline, clonidine, 2-phenethylamine, and amitraz activated the PxOctβ3 receptor, and naphazoline was the most effective. Only metoclopramide and mianserin had significant antagonistic effects on PxOctβ3, whereas yohimbine, phentolamine, and chlorpromazine lacked obvious antagonistic effects. The injection of double-stranded RNA in an RNA interference assay indicated that PxOctβ3 regulates development in P. xylostella. This study demonstrated the pharmacological properties and functions of PxOctβ3 in P. xylostella, thus, providing a theoretical basis for the design of pesticides that target octopamine receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 GASP1 enhances malignant phenotypes of breast cancer cells and decreases their response to paclitaxel by forming a vicious cycle with IGF1/IGF1R signaling pathway "There is a potential correlation between G-protein-coupled receptor-associated sorting protein 1 (GASP1) and breast tumorigenesis. However, its biological function and underlying molecular mechanism in breast cancer have not been clearly delineated. Here, we demonstrated that GASP1 was highly expressed in breast cancers, and patients harboring altered GASP1 showed a worse prognosis than those with wild-type GASP1. Functional studies showed that GASP1 knockout significantly suppressed malignant properties of breast cancer cells, such as inhibition of cell proliferation, colony formation, migration, invasion and xenograft tumor growth in nude mice as well as induction of G1-phase cell cycle arrest, and vice versa. Mechanistically, GASP1 inhibited proteasomal degradation of insulin-like growth factor 1 receptor (IGF1R) by competitively binding to IGF1R with ubiquitin E3 ligase MDM2, thereby activating its downstream signaling pathways such as NF-κB, PI3K/AKT, and MAPK/ERK pathways given their critical roles in breast tumorigenesis and progression. IGF1, in turn, stimulated GASP1 expression by activating the PI3K/AKT pathway, forming a vicious cycle propelling the malignant progression of breast cancer. Besides, we found that GASP1 knockout obviously improved the response of breast cancer cells to paclitaxel. Collectively, this study demonstrates that GASP1 enhances malignant behaviors of breast cancer cells and decreases their cellular response to paclitaxel by interacting with and stabilizing IGF1R, and suggests that it may serve as a valuable prognostic factor and potential therapeutic target in breast cancer." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Experimental studies proposed a direct effect of follicle-stimulating hormone (FSH) on the skeletal metabolism, but results of human studies mainly conducted in females are controversial. The present study aims to investigate the possible role of FSH excess in male bone health, by comparing for the first time primary and central hypogonadism." Read more at the source #DrGPCR #GPCR #IndustryNews

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 pharmaceutical target for pain management. Although the high-resolution crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism remains to be elusive. 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. While the receptor with the crystal ligand (i.e. antagonist naltrindole) maintained the inactive conformation in all three independent simulations, the receptor with ADL5859 was adopting toward the active conformation in three out of six independent simulations. Major conformational differences were located on transmembrane (TM) 5 and 6, as well as intracellular loop 3. Compared to naltrindole, ADL5859 exhibited high conformational flexibility and strong interaction with the transmission switch. The putative key residues (W274, D95, V267, L139, V263, M142, T260, R146, R258 and others) involving in the activation pathway were identified through the conventional molecular switch analysis and a pairwise distance analysis, which provides a short list for experimental mutagenesis study. These insights will facilitate further development of therapeutic agents targeting the DOR.Communicated by Ramaswamy H. Sarma." Read more at the source #DrGPCR #GPCR #IndustryNews

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

September 2022 β2-Adrenergic Receptor Expression and Intracellular Signaling in B Cells Are Highly Dynamic during Collagen-Induced Arthritis "The sympathetic nervous system (SNS) has either a pro-inflammatory or anti-inflammatory effect, depending on the stage of arthritis. In the past, treatment of arthritic B cells with a β2-adrenergic receptor (β2-ADR) agonist has been shown to attenuate arthritis. In this study, the expression and signaling of β2-ADR in B cells during collagen-induced arthritis (CIA) were investigated to provide an explanation of why only B cells from arthritic mice are able to improve CIA. Splenic B cells were isolated via magnetic-activated cell sorting (MACS). Adrenergic receptors on B cells and intracellular β2-ADR downstream molecules (G protein-coupled receptor kinase 2 (GRK-2), β-Arrestin 2, p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB)) were analyzed at different time points in naïve and arthritic B cells with and without stimulation of β2-ADR agonist terbutaline by flow cytometry. β2-ADR-expressing B cells increase during CIA without a change in receptor density. Moreover, we observed a profound downregulation of GRK-2 shortly after induction of arthritis and an increase in β-Arrestin 2 only at late stage of arthritis. The second messengers studied (p38, ERK1/2 and CREB) followed a biphasic course, characterized by a reduction at onset and an increase in established arthritis. Stimulation of CIA B cells with the β-ADR agonist terbutaline increased pp38 MAPK independent of the timepoint, while pERK1/2 and pCREB were enhanced only in the late phase of arthritis. The phosphorylation of p38 MAPK, ERK1/2 and CREB in the late phase of arthritis was associated with increased IL-10 produced by B10 cells. The change of β2-ADR expression and signaling during sustained inflammation might be an integral part of the switch from pro- to anti-inflammatory action of sympathetic mechanisms in late arthritis." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, our structure with S1P5-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family." Read more at the source #DrGPCR #GPCR #IndustryNews