Here we report that neuropeptide S (NPS) signaling in the PVT is necessary for stimulus salience encoding

biotech company with a unique portfolio of CB1 inverse agonists, today announces the appointment of Glenn S. Vraniak served as Chief Financial Officer of Evaxion Biotech A/S, an AI enabled immuno-oncology company

November 2021 Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity

Objective: The goal of this study was to determine the glucometabolic effects of acute activation of Gs signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis. Methods: To address this question, we studied mice that express a Gs-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two Gs-coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β2-adrenergic receptor and CRF2 receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively). Results: Acute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β2-adrenergic and, potentially, CRF2 receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM Gs signaling. Conclusions: Selective activation of Gs signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous Gs-coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release. Read full article

HBx-induced cell cycle acceleration and the subsequent proliferative response via the induction of G1/S transcription factor 1; FBS: fetal bovine serum; GPCRs: G protein-coupled receptors; GST: glutathione S-transferase

TRPM3's best understood function is its role as a peripheral noxious heat sensor in mice. Moreover, the mechanisms underlying regulation of TRPM3 are largely unexplored. However, a clear picture is needed to unravel TRPM3's full potential as experimental tool, diagnostic

October 2022 Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the

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

October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric IUPHAR Review 34 "Functional advances have guided our knowledge of physiological and fatal pathological mechanisms dynamics of AngII receptors and how structural knowledge can be transformative in understanding the mechanisms

November 2022 Deciphering the signaling mechanisms of β-arrestin1 and β-arrestin2 in regulation of cancer overview of the role of β-arrestins with a primary emphasis on the signaling processes which underlie the mechanism

October 2022 "While the role of G-protein-coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1-4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH-Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4-Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4-4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4-4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4-4) may become a promising candidate for future therapeutic cancer treatment." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Mechanism of enhanced sensitivity of mutated β-adrenergic-like octopamine receptor to amitraz However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity

August 2022 Deciphering the signaling mechanisms of β-arrestin1 and β-arrestin2 in regulation of cancer overview of the role of β-arrestins with a primary emphasis on the signaling processes which underlie the mechanism

September 2022 To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism

Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been

As the mechanisms underlying spatial bias in GPCR signaling involve both temporal and spatial components The clinical relevance of understanding these signaling mechanism is linked with the fact that dysregulation Furthermore, targeting GPCRs in specific cellular compartments requires precise delivery mechanisms to , S. Mechanisms Associated with Activation of Intracellular Metabotropic Glutamate Receptor, mGluR5.

., Odongo, S., Radwanska, M., & Magez, S. (2023). pharmacology and toxicology, 57, 19–37. https://doi.org/10.1146/annurev-pharmtox-010716-104710 Rasmussen, S. S., Devree, B. T., Rosenbaum, D. M., Thian, F. S., Kobilka, T. S., Schnapp, A., Konetzki, I., Sunahara, R. K., Gellman, S. H., Pautsch, A., Steyaert, J., Weis, W. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E.

ERK signaling, tightly regulated through feedback mechanisms and spatial localisation within the cell References Eishingdrelo, H., & Kongsamut, S. (2013). Wei, H., Ahn, S., Shenoy, S. K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R.

efforts aim to accelerate drug discovery and improve clinical success Agreement to utilize Exscientia ’s develop up to 15 novel small molecule candidates across oncology and immunology, leveraging Exscientia ’s The companies have been working together since 2016 and in 2019, Sanofi in-licensed Exscientia ’s novel

a recent issue of Molecular Cell, Fonseca et al. identified a previously overlooked desensitization mechanism Agonist activation of the β2-adrenoceptor (β2AR) causes its S-nitrosylation that is required for the Eliminating β2AR S-nitrosylation by mutation of C265 augments β2AR protein kinase A signaling, enables

S. (2002) National Human Genome Research Institute. S., Caron, M. G., Lefkowitz, R. J., & Strader, C. D. (1986). Molecular pharmacology, 63(6), 1256–1272. https://doi.org/10.1124/mol.63.6.1256 Syed Haneef, S. ., & Ranganathan, S. (2019). Structural bioinformatics analysis of variants on GPCR function.

explored how growth factors can modulate canonical G protein signaling, shedding light on molecular mechanisms Notably, the Y320F mutation restored some signaling capabilities, emphasizing Tyr320's role in membrane Mechanisms of Inhibition: The study identified three distinct mechanisms by which phosphorylation inhibits In conclusion, this research elucidates the molecular mechanisms by which growth factors influence G Reference Roy, S., Sinha, S., Silas, A. J., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024).

First, we switched GPCRs between S. pombe and the closely related species Schizosaccharomyces octosporus , which showed that SoMam2 (Mam2 of S. octosporus) is partially functional in S. pombe, whereas SoMap3 (Map3 of S. octosporus) is not interchangeable.

The diversity in GPCR signaling regulation suggests an individualized control mechanism. S. F et al. 2021, Chen, H. et al. 2022). S. et al. 2022). S. F. et al. 2021). Nonetheless, there is an ongoing need to delve deeper into the intricate mechanisms governing GPCR activation

., Tectonic ’s SVP, Head of Research.

while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand(s) example of a dual-function receptor that directly regulates both cell migration and scavenging (Volpe S. scavenging is independent of G proteins, GRKs, arrestins, as well as clathrin, which is a different mechanism the potential implications of its inhibition, an in-depth understanding of the underlying regulatory mechanisms

August 2022 "Aims: The pathophysiological mechanism(s) underlying non-alcoholic fatty liver disease (