Search Results

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 "Single-molecule counting techniques enable a precise determination of the intracellular abundance and stoichiometry of proteins and macromolecular complexes. These details are often challenging to quantitatively assess yet are essential for our understanding of cellular function. Consider G-protein-coupled receptors-an expansive class of transmembrane signaling proteins that participate in many vital physiological functions making them a popular target for drug development. While early evidence for the role of oligomerization in receptor signaling came from ensemble biochemical and biophysical assays, innovations in single-molecule measurements are now driving a paradigm shift in our understanding of its relevance. Here, we review recent developments in single-molecule counting with a focus on photobleaching step counting and the emerging technique of quantitative single-molecule localization microscopy-with a particular emphasis on the potential for these techniques to advance our understanding of the role of oligomerization in G-protein-coupled receptor signaling." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of Cannabinoid CB1 Receptor Bound to a Negative Allosteric Modulator, ORG27569, and Analogs "A growing number of G-protein-coupled receptor (GPCR) structures reveal novel transmembrane lipid-exposed allosteric sites. Ligands must first partition into the surrounding membrane and take lipid paths to these sites. Remarkably, a significant part of the bound ligands appears exposed to the membrane lipids. The experimental structures do not usually account for the surrounding lipids, and their apparent contribution to ligand access and binding is often overlooked and poorly understood. Using classical and enhanced molecular dynamics simulations, we show that membrane lipids are critical in the access and binding of ORG27569 and its analogs at the transmembrane site of cannabinoid CB1 receptor. The observed differences in the binding affinity and cooperativity arise from the functional groups that interact primarily with lipids. Our results demonstrate the significance of incorporating membrane lipids as an integral component of transmembrane sites for accurate characterization, binding-affinity calculations, and lead optimization in drug discovery." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is unclear. Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory cortex, which show differential responsiveness to locomotion. We 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 by α1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to PFC function though neuromodulator receptor crosstalk." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Novel Therapies for Cardiometabolic Disease: Recent Findings in Studies with Hormone Peptide-Derived G Protein Coupled Receptor Agonists "The increasing prevalence of obesity and type 2 diabetes (T2DM) is provoking an important socioeconomic burden mainly in the form of cardiovascular disease (CVD). One successful strategy is the so-called metabolic surgery whose beneficial effects are beyond dietary restrictions and weight loss. One key underlying mechanism behind this surgery is the cooperative improved action of the preproglucagon-derived hormones, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) which exert their functions through G protein-coupled receptors (GPCR). Great success has been reached with therapies based on the GLP-1 receptor monoagonism; therefore, a logical and rational approach is the use of the dual and triagonism of GCPC to achieve complete metabolic homeostasis. The present review describes novel findings regarding the complex biology of the preproglucagon-derived hormones, their signaling, and the drug development of their analogues, especially those acting as dual and triagonists. Moreover, the main investigations into animal models and ongoing clinical trials using these unimolecular dual and triagonists are included which have demonstrated their safety, efficacy, and beneficial effects on the CV system. These therapeutic strategies could greatly impact the treatment of CVD with unprecedented benefits which will be revealed in the next years." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression "Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism remains unclear. The network pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms of action in the treatment of depression. Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone, and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. KEGG pathway analysis highlighted the most significant pathways associated with depression treatment, including neuroactive ligand-receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological process of GPCR signal transduction, hormone metabolism and nerve cell apoptosis. Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed greater binding ability with key antidepressant target 5-HTR. In conclusion, this study preliminarily revealed key active components in KXS, including Gomisin B, Asarone, Ginsenoside Rg1, Polygalaxanthone III and Pachymic acid, could interact with multiple targets (5-HTR, DR, ADRA, AR, ESR, NR3C1) and modulate the activation of multiple pathways (Neuroactive ligand -receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway)." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Protease activated receptors (PARs) are among the first receptors shown to transactivate other receptors: noticeably, these interactions are not limited to members of the same family, but involve receptors as diverse as receptor kinases, prostanoid receptors, purinergic receptors and ionic channels among others. In this review, we will focus on the evidence for PAR interactions with members of their own family, as well as with other types of receptors. We will discuss recent evidence as well as what we consider as emerging areas to explore; from the signalling pathways triggered, to the physiological and pathological relevance of these interactions, since this additional level of molecular cross-talk between receptors and signaling pathways is only beginning to be explored and represents a novel mechanism providing diversity to receptor function and play important roles in physiology and disease." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Numerous physiological processes in insects are tightly regulated by neuropeptides and their receptors. Although they form an ancient signaling system, there is still a great deal of variety in neuropeptides and their receptors among different species within the same order. Neuropeptides and their receptors have been documented in many hemipteran insects, but the differences among them have been poorly characterized. Commercial grapevines worldwide are plagued by the bug Daktulosphaira vitifoliae (Hemiptera: Sternorrhyncha). Here, 33 neuropeptide precursors and 48 putative neuropeptide G protein-coupled receptor (GPCR) genes were identified in D. vitifoliae. Their expression profiles at the probe and feeding stages reflected potential regulatory roles in probe behavior. By comparison, we found that the Releasing Hormone-Related Peptides (GnRHs) system of Sternorrhyncha was differentiated from those of the other 2 suborders in Hemiptera. Independent secondary losses of the adipokinetic hormone/corazonin-related peptide receptor (ACP) and corazonin (CRZ) occurred during the evolution of Sternorrhyncha. Additionally, we discovered that the neuropeptide signaling systems of Sternorrhyncha were very different from those of Heteroptera and Auchenorrhyncha, which was consistent with Sternorrhyncha's phylogenetic position at the base of the order. This research provides more knowledge on neuropeptide systems and sets the groundwork for the creation of novel D. vitifoliae management strategies that specifically target these signaling pathways." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)-activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist-mediated activation mechanism "The mechanistic details of the tethered agonist mode of activation for the adhesion GPCR ADGRF5/GPR116 have not been completely deciphered. We set out to investigate the physiological importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro and in vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for function in vivo. Using site-directed mutagenesis and species-swapping approaches, we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane 7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Over three decades of research have provided thorough insights into G protein-coupled receptor (GPCR) regulation. In 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 receptor to internalize and desensitize. Eliminating β2AR S-nitrosylation by mutation of C265 augments β2AR protein kinase A signaling, enables β2AR nitric oxide (NO) signaling, renders mice resistant to bronchoconstriction, and protects mice from allergen-induced asthma." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Design and validation of recombinant protein standards for quantitative Western blot analysis of cannabinoid CB1 receptor density in cell membranes: an alternative to radioligand binding methods "Background: Replacement of radioligand binding assays with antibody-antigen interaction-based approaches for quantitative analysis of G protein-coupled receptor (GPCR) levels requires the use of purified protein standards containing the antigen. GPCRs in general and cannabinoid CB1 receptor in particular show a progressive tendency to aggregate and precipitate in aqueous solution outside of their biological context due to the low solubility that the hydrophobic nature imprinted by their seven transmembrane domains. This renders full-length recombinant GPCRs useless for analytical purposes, a problem that can be overcome by engineering soluble recombinant fragments of the receptor containing the antigen. Results: Here we generated highly soluble and stable recombinant protein constructs GST-CB1414-472 and GST-CB1414-442 containing much of the human CB1 receptor C-terminal tail for use as standard and negative control, respectively, in quantitative Western blot analysis of CB1 receptor expression on crude synaptosomes of the adult rat brain cortex. To this end we used three different antibodies, all raised against a peptide comprising the C-terminal residues 443-473 of the mouse CB1 receptor that corresponds to residues 442-472 in the human homolog. Estimated values of CB1 receptor density obtained by quantitative Western blot were of the same order of magnitude but slightly higher than values obtained by the radioligand saturation binding assay." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Genome-scale CRISPR screening reveals that C3aR signaling is critical for rapid capture of fungi by macrophages "The fungal pathogen Histoplasma capsulatum (Hc) invades, replicates within, and destroys macrophages. To interrogate the molecular mechanisms underlying this interaction, we conducted a host-directed CRISPR-Cas9 screen and identified 361 genes that modify macrophage susceptibility to Hc infection, greatly expanding our understanding of host gene networks targeted by Hc. We identified pathways that have not been previously implicated in Hc interaction with macrophages, including the ragulator complex (involved in nutrient stress sensing), glycosylation enzymes, protein degradation machinery, mitochondrial respiration genes, solute transporters, and the ER membrane complex (EMC). The highest scoring protective hits included the complement C3a receptor (C3aR), a G-protein coupled receptor (GPCR) that recognizes the complement fragment C3a. Although it is known that complement components react with the fungal surface, leading to opsonization and release of small peptide fragments such as C3a, a role for C3aR in macrophage interactions with fungi has not been elucidated. We demonstrated that whereas C3aR is dispensable for macrophage phagocytosis of bacteria and latex beads, it is critical for optimal macrophage capture of pathogenic fungi, including Hc, the ubiquitous fungal pathogen Candida albicans, and the causative agent of Valley Fever Coccidioides posadasii. We showed that C3aR localizes to the early phagosome during Hc infection where it coordinates the formation of actin-rich membrane protrusions that promote Hc capture. We also showed that the EMC promotes surface expression of C3aR, likely explaining its identification in our screen. Taken together, our results provide new insight into host processes that affect Hc-macrophage interactions and uncover a novel and specific role for C3aR in macrophage recognition of fungi." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies "Biased agonism is a frontier field in GPCR research. Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing receptor (CaSR) autoantibodies, to date, showing either simple blocking or biased properties (i.e., stimulatory or blocking effects on different downstream signaling pathways). This emphasizes the importance of the Gi/o (pertussis toxin-sensitive G proteins, whose βγ subunits activate multiple signals, including ERK1/2) in regulating parathyroid hormone secretion. We here describe 3 patients with symptomatic AHH who shared characteristics with the 2 cases we previously reported as follows: (a) elderly (74-87 years at diagnosis), (b) male, (c) unexpectedly showed no other autoimmune diseases, (d) showed spontaneously fluctuating Ca levels from approximately normal to near fatally high ranges, (e) acute exacerbations could be successfully treated with prednisolone and/or calcimimetics, (f) the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR, and (g) were likely to be conformational (i.e., recognizing and, thereby, stabilizing a unique active conformation of CaSR that activates Gq/11, activating phosphatidylinositol turnover, but not Gi/o). Our observations with these prominent commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which the biased agonism of GPCRs operate." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Perturbation of the endocannabinoid system can have profound effects on immune function and synaptic plasticity. Microglia are one of few cell types with a self-contained endocannabinoid system and are positioned at the interface between the immune system and the central nervous system. Past work has produced conflicting results with respect to the effects of pro-inflammatory conditions on the microglial endocannabinoid system. Thus, we systematically investigated the relationship between the concentration of two distinct pro-inflammatory stimuli, lipopolysaccharide and interferon gamma, on the abundance of components of the endocannabinoid system within microglia. Here we show that lipopolysaccharide and interferon gamma influence messenger RNA abundances of the microglial endocannabinoid system in a concentration-dependent manner. Furthermore, we demonstrate that the efficacy of different synthetic cannabinoid treatments with respect to inhibition of microglia nitric oxide release is dependent on the concentration and type of pro-inflammatory stimuli presented to the microglia. This indicates that different pro-inflammatory stimuli influence the capacity of microglia to synthesize, degrade, and respond to cannabinoids which has implications for the development of cannabinoid-based treatments for neuroinflammation." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "The activity of dopamine neurons is dependent on both intrinsic properties and afferent projections. One potent form of inhibition is mediated by the activation of two inhibitory G protein-coupled receptors, D2 and GABAB receptors. Each of these receptors activates G protein-coupled inwardly rectifying potassium (GIRK) channels. Recordings in brain slices have shown that co-activation using saturating concentrations of agonists results in occlusion of the GIRK current. The present study examined the interaction between D2 and GABAB receptors using transient applications of sub-saturating concentrations of agonists where the co-application of one agonist resulted in both facilitation and inhibition (desensitization) of the other. The heterologous facilitation was modelled based on the known cooperative interaction between the G protein βγ subunits and GIRK channels. The results indicate that a low tonic level of G βγ results in facilitation of GIRK current and a high level of G βγ results in occlusion. The kinetics of the current induced by transient receptor activation is prolonged in each case. The results suggest that the cooperative interaction between G βγ subunits and GIRK channels determines both the amplitude and kinetics of GPCR-dependent current. KEY POINTS: Inhibitory D2 and GABAB receptors modulate dopamine neuron activity through shared G protein-coupled inwardly rectifying potassium (GIRK) channels. This study reports robust bidirectional interactions between these two converging receptor pathways. Coincident activation of D2 and GABAB receptors leads to facilitation of GIRK channel currents, augmenting both amplitude and prolonging the duration of phasic responses. Activation of either D2 or GABAB receptors also acutely desensitized the GIRK channel current induced by D2 receptor activation that rapidly recovers following termination of desensitizing stimulus. Results demonstrate that the activity of either G protein-coupled receptor system must be considered in the context of other G protein-coupled receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Study of small molecule binding to live cells provides important information on the characterization of ligands pharmacologically. Here we developed and validated a label-free, liquid chromatography-mass spectrometry (LC-MS) based cell binding assay, using centrifugation to separate binders from non-binders. This assay was applied to various target classes, with particular emphasis on those for which protein-based binding assay can be difficult to achieve. In one example, to study a G protein coupled receptor (GPCR), we used one antagonist as probe and multiple other antagonists as competitor ligands. Binding of the probe was confirmed to be specific and saturable, reaching a fast equilibrium. Competition binding analysis by titration of five known ligands suggested a good correlation with their inhibition potency. In another example, this assay was applied to an ion channel target with its agonists, of which the determined binding affinity was consistent with functional assays. This versatile method allows quantitative characterization of ligand binding to cell surface expressed targets in a physiologically relevant environment." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Cholesterol-Dependent Dynamics of the Serotonin1A Receptor Utilizing Single Particle Tracking: Analysis of Diffusion Modes "G protein-coupled receptors (GPCRs) are signaling hubs in cell membranes that regulate a wide range of physiological processes and are popular drug targets. Serotonin1A receptors are important members of the GPCR family and are implicated in neuropsychiatric disorders. Cholesterol is a key constituent of higher eukaryotic membranes and is believed to contribute to the segregated distribution of membrane constituents into domains. To explore the role of cholesterol in lateral dynamics of GPCRs, we utilized single particle tracking (SPT) to monitor diffusion of serotonin1A receptors under acute and chronic cholesterol-depleted conditions. Our results show that the short-term diffusion coefficient of the receptor decreases upon cholesterol depletion, irrespective of the method of cholesterol depletion. Analysis of SPT trajectories revealed that relative populations of receptors undergoing various modes of diffusion change upon cholesterol depletion. Notably, in cholesterol-depleted cells, we observed an increase in the confined population of the receptor accompanied by a reduction in diffusion coefficient for chronic cholesterol depletion. These results are supported by our recent work and present observations that show polymerization of G-actin in response to chronic cholesterol depletion. Taken together, our results bring out the interdependence of cholesterol and actin cytoskeleton in regulating diffusion of GPCRs in membranes." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "G protein-coupled receptors (GPCRs) are of considerable interest due to their importance in a wide range of physiological functions and in a large number of Food and Drug Administration (FDA)-approved drugs as therapeutic entities. With continued study of their function and mechanism of action, there is a greater understanding of how effector molecules interact with a receptor to initiate downstream effector signaling. This review aims to explore the signaling pathways, dynamic structures, and physiological relevance in the cardiovascular system of the three most important GPCR signaling effectors: heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. We will first summarize their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. As new technologies are developed and applied to studying GPCR structure and their downstream effectors, there is increasing appreciation for the elegance of the regulatory mechanisms that mediate intracellular signaling and function." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Pepducins are small-lipidated peptides designed from the intracellular loops of G protein-coupled receptors (GPCRs) that act in an allosteric manner to modulate the activity of GPCRs. Over the past 2 decades, pepducins have progressed initially from pharmacologic tools used to manipulate GPCR activity in an orthosteric site-independent manner to compounds with therapeutic potential that have even been used safely in phase 1 and 2 clinical trials in human subjects. The effect of pepducins at their cognate receptors has been shown to vary between antagonist, partial agonist, and biased agonist outcomes in various primary and clonal cell systems, with even small changes in amino acid sequence altering these properties and their receptor selectivity. To date, pepducins designed from numerous GPCRs have been studied for their impact on pathologic conditions, including cardiovascular diseases such as thrombosis, myocardial infarction, and atherosclerosis. This review will focus in particular on pepducins designed from protease-activated receptors, C-X-C motif chemokine receptors, formyl peptide receptors, and the β2-adrenergic receptor. We will discuss the historic context of pepducin development for each receptor, as well as the structural, signaling, pathophysiologic consequences, and therapeutic potential for each pepducin class." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis "Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "The cAMP-dependent protein kinase (PKA) system represents a primary cell-signaling pathway throughout systems and across species. PKA facilitates the actions of hormones, neurotransmitters and other signaling molecules that bind G-protein coupled receptors (GPCR) to modulate cAMP levels. Through its control of synaptic events, exocytosis, transcriptional regulation, and more, PKA signaling regulates cellular metabolism and emotional and stress responses making it integral in the maintenance and dysregulation of energy homeostasis. Neural PKA signaling is regulated by afferent and peripheral efferent signals that link specific neural cell populations to the regulation of metabolic processes in adipose tissue, liver, pancreas, adrenal, skeletal muscle, and gut. Mouse models have provided invaluable information on the roles for PKA subunits in brain and key metabolic organs. While limited, human studies infer differential regulation of the PKA system in obese compared to lean individuals. Variants identified in PKA subunit genes cause Cushing syndrome that is characterized by metabolic dysregulation associated with endogenous glucocorticoid excess." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Background: Uncoupling proteins (UCPs) are unpaired electron carriers that uncouple oxygen intake by the electron transport chain from ATP production in the inner membrane of the mitochondria. The physiological activities of UCPs have been hotly contested, and the involvement of UCPs in the pathogenesis and progression of diabetes mellitus is among the greatest concerns. UCPs are hypothesised to be triggered by superoxide and then reduce mitochondrial free radical production, potentially protecting diabetes mellitus patients who are experiencing oxidative stress. Objectives: The objectives of the study are to find out the newest ways to treat diabetes mellitus through protein uncoupling." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein or β-arrestin signaling pathways, are leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer's disease (AD), biased GPCR signaling is a largely unexplored area of investigation in AD. Our previous work demonstrated that GPR3-mediated β-arrestin signaling modulates amyloid-β (Aβ) generation in vitro and that Gpr3 deficiency ameliorates Aβ pathology in vivo. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein signaling. Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological consequences of selective elimination of GPR3-mediated β-arrestin signaling in vivo. In contrast to Gpr3-deficient mice, G protein-biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We further determined that G protein-biased signaling reduces soluble Aβ levels and leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model. The changes in amyloid pathology are accompanied by robust microglial and astrocytic hypertrophy, which suggest a protective glial response that may limit amyloid plaque development in G protein-biased GPR3 AD mice. Collectively, these studies indicate that GPR3-mediated G protein and β-arrestin signaling produce discrete and separable effects and provide proof of concept for the development of safer GPCR-targeting therapeutics with more directed pharmacological action for AD." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics of ligands targeting G-protein-coupled receptors "Recently, academic and industrial scientific communities involved in kinetics-based drug development have become immensely interested in predicting the drug target residence time. Screening drug candidates in terms of their computationally predicted residence times, which is a measure of drug efficacy in vivo, and simultaneously assessing computational binding affinities are becoming inevitable. Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Here, we have implemented an optimized approach of combining the data derived from steered molecular dynamics simulations and the Bell-Evans model to predict the absolute residence times of the antagonist ZMA241385 and agonist NECA that target the A2A adenosine receptor of the G-protein-coupled receptor (GPCR) protein family. We have predicted the absolute ligand residence times on the timescale of seconds. However, our predictions were many folds shorter than those determined experimentally. Additionally, we calculated the thermodynamics of ligand binding in terms of ligand binding energies and the per-residue contribution of the receptor. Subsequently, binding pocket hotspot residues that would be important for further computational mutagenesis studies were identified. In the experiment, similar sets of residues were found to be in significant contact with both ligands under study. Our results build a strong foundation for further improvement of our approach by rationalizing the kinetics of ligand unbinding with the thermodynamics of ligand binding." Read more at the source #DrGPCR #GPCR #IndustryNews

☕ We are excited to announce our rescheduled Dr. GPCR Virtual Cafe session with Dr. Matthew E. on Friday, October 7th at 1 PM ET. Don't miss the chance to listen to his latest research on the field. It's a great opportunity to get warmed up for the upcoming Summit starting the next Monday. Get your ticket today on Eventbrite! ➡https://bit.ly/3CmntVn

We are postponing the Dr. GPCR Virtual Cafe with Matthew Eddy scheduled for tomorrow (Sep 29th, 2022) due to Hurricane Ian that is affecting Florida. We will provide a new rescheduling date soon. #gpcr #drgpcr

September 2022 Cannabinoid type-2 receptors: An emerging target for regulating schizophrenia-relevant brain circuits "Although the cannabinoid type-2 receptor (CB2) is highly expressed in the immune system, emerging evidence points to CB2 playing a key role in regulating neuronal function in the central nervous system. Recent anatomical studies, combined with electrophysiological studies, indicate that CB2 receptors are expressed in specific dopaminergic and glutamatergic brain circuits that are hyperactive in schizophrenia patients. The ability of CB2 receptors to inhibit dopaminergic and hippocampal circuits, combined with the anti-inflammatory effects of CB2 receptor activation, make this receptor an intriguing target for treating schizophrenia, a disease where novel interventions that move beyond dopamine receptor antagonists are desperately needed. The development of new CB2-related pharmacological and genetic tools, including the first small molecule positive allosteric modulator of CB2 receptors, has greatly advanced our understanding of this receptor. While more work is needed to further elucidate the translational value of selectively targeting CB2 receptors with respect to schizophrenia, the studies discussed below could suggest that CB2 receptors are anatomically located in schizophrenia-relevant circuits, where the physiological consequence of CB2 receptor activation could correct circuit-based deficits commonly associated with positive and cognitive deficits." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealized, therapeutic potential. Promising preclinical data support the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such, not optimal for clinical application due to unfavorable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trials. We review the current state of CB2 ligand development and progress in optimizing physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds." Read more at the source #DrGPCR #GPCR #IndustryNews