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October 2022 "Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT2A receptor (5-HT2AR). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) - a mouse behavioral proxy of human psychedelic potential - in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) - a 5-HT2AR antagonist - fully prevented DOI-induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP1) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes - brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HT2AR agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research." Read more at the source #DrGPCR #GPCR #IndustryNews

GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases. Read full article

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

Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor CXCR4 WHIM syndrome is a rare immunodeficiency disorder that is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. Here, we report on a new WHIM syndrome mutation that results in a frame shift within the codon for Ser339 (S339fs5) and compare the properties of S339fs5 with wild type CXCR4 and a previously identified WHIM syndrome mutant, R334X. The S339fs5 and R334X mutants exhibited significantly increased signaling compared to wild type CXCR4 including agonist-promoted calcium flux and extracellular signal-regulated kinase activation. This increase is at least partially due to a significant decrease in agonist-promoted phosphorylation, β-arrestin binding, and endocytosis of S339fs5 and R334X compared to wild type CXCR4. Interestingly, there were also significant differences in receptor degradation, with S339fs5 having a very high basal level of degradation compared to that of R334X and wild type CXCR4. In contrast to wild type CXCR4, both R334X and S339fs5 were largely insensitive to CXCL12-promoted degradation. Moreover, while basal and agonist-promoted degradation of wild type CXCR4 was effectively inhibited by the CXCR4 antagonist TE-14016, this had no effect on the degradation of the WHIM mutants. Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, that promotes enhanced signaling, reduced phosphorylation, β-arrestin binding and endocytosis, and a very high basal rate of degradation that is not protected by antagonist treatment. Read full article

G protein-coupled receptors (GPCRs) are a vast family of membrane-bound proteins crucial for transmitting the initial GPCR-G protein association step, ensuring precise downstream signalling activation. avoiding interactions with non-cognate G proteins [1]. prepare the GPCR in a manner that optimizes subsequent cognate G protein activation. landscape where non-cognate G proteins play a critical preparatory role.

Human cells express over 800 G-protein-coupled receptors (GPCRs) to facilitate communication with the Capturing the dynamics of GPCR activation has always been a challenge because G protein activation in Concurrently, the α1 helix extends, propagating structural changes throughout the G protein. Physiological roles of G protein-coupled receptor kinases and arrestins. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature (2024).

One fascinating aspect of the cellular signaling network is the crosstalk between G protein-coupled receptors involvement in a myriad of physiological processes, mediate mostly signaling through heterotrimeric G this study was: How do growth factors, specifically through RTKs, modulate canonical heterotrimeric G The researchers focused on the phosphorylation of the G protein subunit Gαi at specific residues within Signaling Pathway Segregation: Phosphorylation events in the interdomain cleft and P loop uncouple G

G protein-coupled receptors (GPCRs) are integral membrane proteins crucial for sensing extracellular Central to GPCR function are G proteins, comprising subfamilies such as Gs, Gi/o, Gq/11, and G12/13, and a G protein detector tagged with an Nluc donor. Gilman, A.G., G proteins: transducers of receptor-generated signals.  Wan, Q., et al., Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. 

CXV: The Class F of G Protein-Coupled Receptors Yusman Manchanda, Dr. Alejandra Tomas, et al. for their research on Engineered mini-G proteins block the internalization of Jianming Han, Tao Che for their analysis of GPCR-G protein selectivity revealed by structural pharmacology Drs Christopher Langmead,  Gregory Stewart, et al. for their study on Molecular insights into orphan G GPCR Activation and Signaling GPCR-MAPK signaling pathways underpin fitness trade-offs in whitefly G

G protein-coupled receptors (GPCRs) are membrane-bound proteins that sense external stimuli and relay As a result, dimerized SecR receptors exhibit higher rates of G protein activation and release, improving Bouvier, M., Oligomerization of G-protein-coupled transmitter receptors.   Graaf, C., et al., Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March Wootten, D., et al., Allostery and Biased Agonism at Class B G Protein-Coupled Receptors.  

This Week’s Highlights: G protein-coupled receptor (GPCR) pharmacogenomics Miles D Thompson , David Reiner-Link , Alessandro Berghella , Brinda K Rana , G Enrico Rovati , Valerie Capra , Caroline M Gorvin Joshua Levitz , Ben Jones , Johannes Broichhagen Design of allosteric modulators that change GPCR G Protease-Activated Receptor-1 IgG Autoantibodies in Patients with COVID-19 Signaling by neutrophil G GPTrans: A Biological Language Model-Based Approach for Predicting Disease-Associated Mutations in G

G., Lefkowitz, R. J., & Strader, C. D. (1986). G., & Schiöth, H. B. (2003). The G-protein-coupled receptors in the human genome form five main families. M., Pérez-Hernández, G., Batebi, H., Gao, Y., Eskici, G., Seven, A. W., & Skiniotis, G. (2023).

In all these situations, chemokines interact with seven-transmembrane chemokine-type G protein-coupled In humans there are approximately 45 chemokines, 19 chemotactic or G-protein coupled chemokine receptors availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical G J.; Graham, G. J., 2013). This study revealed that CCR2 scavenging is independent of G proteins, GRKs, arrestins, as well as clathrin

Mikel Garcia-Marcos for their work on Get ready to sharpen your tools:A short guide to heterotrimeric G Sokrat, Michel Bouvier, et al. for their study on the Role of the V2R-βarrestin-Gβγ complex in promoting G the chagas disease vector Rhodnius Prolixus (Stål) Role of the V2R-βarrestin-Gβγ complex in promoting G as Potential Drugs for Chronic Myeloid Leukemia Methods & Updates in GPCR Research High-throughput G GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease Relevance of G

al., for their work on Conformation- and activation-based BRET sensors differentially report on GPCR-G Samuel Liu, Preston Anderson, Sudarshan Rajagopal, Robert Lefkowitz, Howard Rockman for their review G scaffolding proteins required for Shh-mediated axon guidance GPCRs in Oncology and Immunology Regulator of G from Bacillusaltitudinis induces ROS-dependent apoptosis in ovarian cancer cells by targeting PAR-1 G protein coupling Reviews, GPCRs, and more Proteome-wide analysis reveals G protein-coupled receptor-like

Adhesion GPCRs A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer GPCR Activation and Signaling The TAS1R2 G-protein-coupled receptor is an ambient polymerase II degradation Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors Kinetic Model for the Desensitization of G Protein-Coupled Receptor RNA-seq in mouse mammary epithelial cells GPCR Binders, Drugs, and more Structure-based identification of a G

Gonzalez-Hernandez, Hermany Munguba, Joshua Levitz for their work on Emerging modes of regulation of neuromodulatory G GPCR Activation and Signaling Emerging modes of regulation of neuromodulatory G protein-coupled receptors Astrocytic PAR1 and mGluR2/3 control synaptic glutamate time course at hippocampal CA1 synapses Regulator of G dorsolateral striatum of adult male mice Methods & Updates in GPCR Research RNA therapeutics in targeting G suppress hormones GPCR Events, Meetings, and Webinars June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein

Garcia-Marcos for their work on Smooth operator(s): dialing up and down neurotransmitter responses by G-protein László Hunyady for their research on Functional consequences of spatial, temporal and ligand bias of G Fine-Tuning of GPCR Functions Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors cancer nanomedicines: from RNA sequencing data analysis to in vitro validation Signaling by Neutrophil G

selectivity of the Ca2+-sensing receptor GPCRs in Cardiology, Endocrinology, and Taste G protein-coupled Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries GPCRs development updates Methods & Updates in GPCR Research GPCR-BERT: Interpreting Sequential Design of G Protein-Coupled Receptors Using Protein Language Models Scaling up Functional Analyses of the G Protein-Coupled Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G

One potent form of inhibition is mediated by the activation of two inhibitory G protein-coupled receptors Each of these receptors activates G protein-coupled inwardly rectifying potassium (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. in the context of other G protein-coupled receptors."

Notably, G-protein-coupled receptors (GPCRs), representing the biggest drug target, have been revealed Historically, drug discovery efforts targeting GPCRs focused on G-protein-dependent signaling pathways Recent research has unveiled the emergence of G-protein-independent pathways, particularly those involving significant in drug discovery (Wei et al., 2003). β-arrestins, traditionally seen as terminators of G-protein Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular

Mutational Scanning for Enhanced Drug Discovery Cam Sinh Lu GPCR-BSD: a database of binding sites of human G-protein receptor potential canonical 3 ion channel Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling The voltage sensitivity of G-protein coupled receptors: Unraveling Affinity of Hemocyte Membrane Preparations of Manduca sexta and Identification of the Receptor-Associated G Structural and Molecular Insights into GPCR Function GPCR-BSD: a database of binding sites of human G-protein

Adhesion GPCRs The adhesion G-protein-coupled receptor mayo/CG11318 controls midgut development in Drosophila development and diseases GPCR Activation and Signaling Proinflammatory chemokine CXCL14 activates MAS-related G regeneration GPCRs in Neuroscience Astrocyte growth is driven by the Tre1/S1pr1 phospholipid-binding G Characterization of the real-time internalization of nine GPCRs reveals distinct dependence on arrestins and G and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein

Trogdon, J Silvio Gutkind, Edward C Stites, et al., for their study on Systems modeling of oncogenic G-protein activation Chiara D Mancinelli, Joshua Levitz, David Eliezer, et al. for their research on Control of G Structural and Molecular Insights into GPCR Function Entropy drives the ligand recognition in G-protein-coupled insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3 Control of G Pharmaceuticals to Report Second Quarter 2024 Financial Results on August 8, 2024 Dynamic nature of G-protein

crucial for understanding the diverse signaling outcomes mediated by different receptors including G In the endosomes, sustained G protein signaling has been associated with prolonged interactions between GPCRs, G proteins, and arrestins on endosomal membranes3,4. of stable complexes between GPCRs and signaling effectors on endosomes supports multiple rounds of G Nuclear G-protein-coupled receptors as putative novel pharmacological targets.

G.; Ishiguro, H.; Horiuchi, Y.; Onaivi, E. S. -H.; Wu, Y.; Wu, L.; Popov, P.; Benchama, O.; Zvonok, N.; Locke, K.; Qu, L.; Han, G. W.; Iyer, M. G.; Manera, C. A.; Mangiatordi, G. F.; Nicolotti, O.; Perrone, M. G.; Brea, J.; Loza, M. G.; Millet, R.; Goossens, J.-F.; Farce, A.; Chavatte, P.; Poupaert, J. H.; Lambert, D.

Sara Marsango and Graeme Milligan for their research on the Regulation of the pro-inflammatory G protein-coupled biological control GPR84 in physiology-Many functions in many tissues Regulation of the pro-inflammatory G regulation of GPR84 in human neutrophils Large-scale deorphanization of Nematostella vectensis neuropeptide G transfer Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G epigenomic signatures Lipid regulation of the glucagon receptor family Technologies for the discovery of G

What is the molecular basis that determines that GPCRs bind selectively or promiscuously to different G This question led Huang et al., 2022 to investigate the molecular basis involved in G protein-receptor the specific residues involved in ligand selectivity and the interactions involved in the coupling of G interactions are crucial for the coupling of G-proteins to serotonin receptors. the case of promiscuous receptors they found that these receptors shared conserved residues of both G