Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings Below is your Classified GPCR News at a glance for January 16th to January 22th, 2023. GPCR Activation and Signaling Cornichon protein CNIH4 is not essential for mice gametogenesis and fertility. Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling. Cannabinoid tolerance in S426A/S430A x beta-arrestin 2 knock-out double mutant mice. Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation. The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model. Methods & Updates in GPCR Research Mapping of structural arrangement of cells and collective calcium transients: an integrated framework combining live cell imaging using confocal microscopy and UMAP-assisted HDBSCAN-based approach. First metabolic profiling of 4-n-nonylphenol in human liver microsomes by integrated approaches to testing and assessment: Metabolites, pathways, and biological effects. Reviews, GPCRs, and more Olfactory Receptors as an Emerging Chemical Sensing Scaffold. Structural and Molecular Insights into GPCR Function The role of G protein conformation in receptor-G protein selectivity. Targeting in silico GPCR conformations with ultra-large library screening for hit discovery. Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1). Industry News Addex Provides Corporate Update And Financial Guidance Structure Therapeutics Appoints Industry Leaders Eric Dobmeier and Joanne Waldstreicher to its Board of Directors GPCR Therapeutics launches multiple myeloma trial Salipro Biotech is attending the 3rd Advanced Therapy Showcase in Tokyo, Japan, organized by LINK-J Jounce takes the cash under amended deal with Gilead on anti-CCR8 antibody InterAx Biotech Announces the Appointment of Seasoned Pharmaceutical Executive, Dr. Christopher Prior, as CEO and Reports Recent Drug Discovery Highlights Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit, (February 21 - 23, 2023), Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School. (February 20 - March 3, 2023). GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. (April 20 - 21, 2023) SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. (May 14 - 19, 2023) 8th and final ERNEST Meeting in Crete. (May 3 - 7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4 - 8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 - 11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11 - 16, 2023). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7, 2023). GPCR Jobs Postdoctoral Fellow - Molecular Dynamics Postdoc in lipid regulation of GPCRs Postdoctoral positions, biophysics of transporters and GPCRs Chief of Staff Postdoctoral Fellow, Biochemical And Cellular Pharmacology Project Leader, Biology Explore Dr. GPCR Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. Below is your Classified GPCR News at a glance for January 9th to January 15th, 2023. GPCR Activation and Signaling New simulation insights on the structural transition mechanism of Bovine Rhodopsin activation. Mandibulofacial dysostosis with alopecia results from gain-of-ETAR function via allosteric effects on ligand binding. GPCR Binders, Drugs, and more Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design. Protease-activated receptor 2 (PAR2)-targeting peptide derivatives for positron emission tomography (PET) imaging. GPCRs in Cardiology, Endocrinology, and Taste Gender Differences in GRK2 in Cardiovascular Diseases and its Interactions with Estrogen. GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy. Reviews, GPCRs, and more Isolation and functional identification of secretin family G-protein coupled receptor from Y-organ of the mud crab, Scylla olivacea. Structural and Molecular Insights into GPCR Function Thermodynamic architecture and conformational plasticity of GPCRs. Structural Understanding of Peptide-Bound G Protein-Coupled Receptors: Peptide-Target Interactions. Cryo-EM structures of orphan GPR21 signaling complexes. GPCR Allostery: a View from Computational Biology. The molecular associations in clathrin-coated pit regulate β-arrestin-mediated MAPK signaling downstream of μ-opioid receptor. Industry News Trevena Enrolls First Subject in TRV045 Proof-of-Concept Trial Evaluating S1PR Mechanism of Action and Target Engagement Novo Nordisk's GLP-1 for Type II diabetes approved for first-line treatment The Lundbeck Foundation is awarding DKK 174 million in grants to seven ‘mind-bending’ research collaborations GPCR Therapeutics Announces Launch of US Phase 2 Trial of GPC-100 in Multiple Myeloma Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. SLAS2023 International Conference and Exhibition (February 25 - March 1). SLAS 2023 Building Biology in 3D Symposium. (April 20-21, 2023) SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd ERNEST Training School. (February 20 - March 3, 2023). GEM2023. (March 14-17, 2023). 8th and final ERNEST Meeting in Crete. (May 3-7, 2023). The Illuminating the Understudied Druggable Proteome Conference. (June 4-8, 2023). 2023 Molecular Pharmacology (GRS) Seminar GRC. (June 10 -11, 2023). Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. (June 11-16, 2023). 19th World Congress of Basic & Clinical Pharmacology 2023. (July 2 - 7). GPCR Jobs Biotechnology and Biological Sciences Doctoral Training Programme Senior QM Manager Director of Molecular Pharmacology, Discovery Biology Staff Scientist/Senior Staff Scientist, Disease Biology and Translational Sciences Senior Scientist, Drug Metabolism and Pharmacokinetics PhD Opportunity - Investigation Of The Role Of The Formyl Peptide Receptor 2 In Diabetic Retinopathy PhD Opportunity - Novel P2y Receptor Ligands For Drug Discovery Explore Dr. GPCR Ecosystem

Odorant receptors function and expression landscape Odorant receptors (ORs) belong to the G protein-coupled receptor (GPCR) family and are the largest known mammalian gene family with around 900 genes. ORs are highly expressed by olfactory sensory neurons of the nose where they are activated by different odorant molecules which initiate a neuronal response that drives odorant discrimination and perception (Young J. and Trask B. 2002). Higher-resolution analysis of gene expression, including q)RT-PCR, microarray, or relatively new NGS (RNASeq) analyses, have indicated that OR genes are also expressed in non-olfactory tissues including the testis, lung, intestine, skin, heart, and blood, where they can play diverse physiological roles. Although ORs expression is quite stable, the number of ORs expressed in different human tissues is highly variable from more than 60 ORs in the testis and only a few ORs in the liver (Flegel C. et al. 2013; Maßberg D. and Hatt H. 2018). OR4N4 is the most highly expressed OR in human spermatozoa and is an example of a highly and selectively expressed OR, whereas OR51E1 and OR51E2 represent ubiquitously expressed ORs, although there are highly increased in prostate tissue, especially in prostate cancer (Maßberg D. and Hatt H. 2018). Interestingly, olfactory neurons gene expression is very peculiar, and each neuron expresses a single OR gene however, ectopic ORs expression is unlikely to be modulated by this tight mechanism with transcriptomic analysis revealing that while the majority of cancer cells express multiple ORs, tumor cells associated with the nervous system express a single OR gene type (Kalra S. et. al 2020). Physiological functions of ectopically expressed olfactory receptors ORs participate in important cellular processes outside of olfactory system. In the cardiovascular system, ORs have the potential to operate as the main carriers of endogenously and exogenously derived odorants in our body. OR10J5 has been proposed to be a metabolic regulator of cardiac function (Jovancevic N. et. Al 2017) and its activation promotes migration and angiogenesis (Kim S. et. al 2015). In the immune system ORs are expressed in different blood cells where aroma compounds from butter, known ligands for a variety of class I ORs, induce chemotactic behavior in human neutrophils (Geithe C. et al. 2015). OR function has been implicated in myelogenous leukemia where OR2AT4 activation leads to reduced proliferation and enhanced apoptosis of acute myeloid leukemia cells (S Manteniotis et al. 2016). In the gastrointestinal system, ORs may significantly contribute to abnormal bowel functions. In the GI tract OR ligands drive an intracellular cascade that results in enhanced serotonin release (Braun T. et. al 2007), an important regulator of gut peristalsis. In the genito-urinary system, the activation of ORs was shown to influence the motility of spermatozoa (Spehr M. et. al 2003). In the human kidney ORs elicit intracellular Ca2+flux in renal proximal tubule cells via adenylyl cyclase (AC) activity (Kalbe B et. al 2016). OR51E1 and OR51E2, initially assumed to be GPCRs only expressed in prostate tissue, play a role in prostate cancer epithelial cells proliferation via activation by β-ionone which initiates prostate cancer cell cycle arrest (Jones S. et. al 2013). In the nervous system, although there is limited data, it has been suggested that ORs adopt functions in the central nervous system. For example, OR4M1 was proposed to interfere with aberrant tau hyperphosphorylation (Zhao W. et. al 2013). In the respiratory system, the activation of ORs by amyl butyrate and bourgeonal, OR2AG1 and OR1D2 agonists, respectively, impact the contractility of human airway smooth muscle cells (Kalbe B. et. al 2016). In non-small-cell lung cancer OR2J3 activation induced apoptosis and inhibited cell proliferation and migration in long-term stimulus experiments (Kalbe B. et al. 2017). In the skin, OR51E2 was shown to play a role in human melanocyte homeostasis (Gelis L. et. al 2016) and the sandalore-activated receptor OR2AT4 shown to promote human keratinocyte proliferation and migration (Busse D. 2014). Exploring ORs in drug discovery – opportunities and threats Given the functional relevance of ORs in different physiological and pathophysiological contexts, primarily based on the deorphanization of these receptors, with the identified ligands being often synthetic compounds, there has been a growing interest from the scientific community to target this class of GPCRs. However, selection of promising candidates is not an easy task. Due to the diversity of the OR family it will be critical to select potential targets to modulate in a disease setting as ectopic expression of ORs does not always correlate with functionality. In addition, most ORs require olfactory-specific chaperones to be correctly targeted to the surface of heterologous cells (Maßberg D. and Hatt H. 2018) which implies that heterologous expression of ORs is generally more technically challenging compared with expression of nonolfactory GPCRs and also that deorphanization is challenging. Finally, direct evidence that ectopically expressed OR drives pathophysiological processes remains a big bottleneck. In order to target ectopic ORs there is a need to identify selective agonists or antagonists, where the starting point can be using licensed drugs (for drug repurposing) and endogenous ligands. Odorants, the natural ligands, could potentially be used as ligands and particular forms of odorant delivery would be required where selectivity must be carefully evaluated as odoronts tend to bind to various ORs. Selective screening assays for ectopic ORs as well as investment on the structural characterization of these receptors would be of great help to aid drug discovery. The development of antibodies directed towards an OR could either drive receptor inactivation or activation of the receptor to destroy tumor cells or be used in drug delivery. The chimeric antigen receptor T cell therapy could also be a way to target tumor cells expressing ectopic ORs (Naressi R. et. al 2023). Future directions Important directions in ORs research to advance drug discovery include the deorphanization and characterization of relevant ligands, characterization of the function of ORs in vivo, development of in vitro systems for functional assays and the availability of structural information for structure-based drug design. Check the original article at https://pubmed.ncbi.nlm.nih.gov/35999088/ #GPCR #DrGPCR#Ecosystem

Hello Readers👋, We're excited to share our weekly newsletter with you. Keep up-to-date with the latest research and advancements in the field with our convenient, weekly news delivered to your inbox. You can always adjust your email preferences in your account settings. Below is your Classified GPCR News at a glance for January 2nd to January 8th, 2023. GPCR Activation and Signaling Signal Transduction and Gene Regulation in the Endothelium. Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target. GPCR Signaling Measurement and Drug Profiling with an Automated Live-Cell Microscopy System. GPCR Binders, Drugs, and more Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells. GPCRs in Neuroscience Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane. GPCRs in Oncology and Immunology Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway. Methods & Updates in GPCR Research Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs. Structural and Molecular Insights into GPCR Function Structural and functional analyses of a GPCR-inhibited ion channel TRPM3. Industry News Arcoscreen selected by START Lausanne to pitch at the START Global summit on the 23-24th March 2023. Twist Bioscience and Astellas Enter into Multitarget Antibody Discovery Research Collaboration Neurocrine Biosciences and Voyager Therapeutics Enter Strategic Collaboration for Development and Commercialization of Voyager’s GBA1 Program and Other Next-Generation Gene Therapies for Neurological Diseases Crinetics Pharmaceuticals To Present Corporate And Clinical Update At 41st Annual J.P. Morgan Healthcare Conference Neurocrine Biosciences, Inc.'s Director Stephen A. Sherwin Sells 30,000 Shares STALICLA signs agreement with Novartis on neurodevelopmental disorders Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. GPCR Jobs Biotechnology and Biological Sciences Doctoral Training Programme Senior QM Manager Director of Molecular Pharmacology, Discovery Biology Staff Scientist/Senior Staff Scientist, Disease Biology and Translational Sciences Senior Scientist, Drug Metabolism and Pharmacokinetics PhD Opportunity - Investigation Of The Role Of The Formyl Peptide Receptor 2 In Diabetic Retinopathy PhD Opportunity - Novel P2y Receptor Ligands For Drug Discovery Explore Dr. GPCR Ecosystem

Hello Readers👋, Happy New Year! We're excited to be back and share our weekly newsletter! We'll be sending it directly to your inbox every week, so you'll always be the first to know about the latest GPCR news. Below is your Classified GPCR News at a glance for December 19th to January 1st, 2023. GPCR Activation and Signaling Transactivation of receptor tyrosine kinases by purinergic P2Y and adenosine receptors. Ligand recognition and activation of neuromedin U receptor 2. Biased agonists differentially modulate the receptor conformation ensembles in Angiotensin II type 1 receptor. Unusual phototransduction via cross-motif signaling from Gq to adenylyl cyclase in intrinsically photosensitive retinalganglion cells. GPCR Binders, Drugs, and more Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency. Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders. Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor. GPCRs in Cardiology, Endocrinology, and Taste Metabolic depletion of sphingolipids inhibits agonist-induced endocytosis of the serotonin1A receptor. GPCRs in Neuroscience Role of G-Proteins and GPCR-Mediated Signalling in Neuropathophysiology. GPCRs in Oncology and Immunology Clinical, pathophysiologic, genetic and therapeutic progress in Primary Bilateral Macronodular Adrenal Hyperplasia. GPR4 in the pH-dependent migration of melanoma cells in the tumor microenvironment. Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19. Functional Assessment of Cancer-Linked Mutations in Sensitive Regions of Regulators of G Protein Signaling Predicted by Three-Dimensional Missense Tolerance Ratio Analysis. Deletion of macrophage Gpr101 disrupts their phenotype and function dysregulating host immune responses in sterile and infectious inflammation. Methods & Updates in GPCR Research Quantitation of Plasma Membrane (G Protein-Coupled) Receptor Trafficking in Cultured Cells. A robust antibody discovery platform for difficult-to-express G protein-coupled receptors. Reviews, GPCRs, and more Species dependence of A3 adenosine receptor pharmacology and function. Transcriptome profiling of male and female Ascaris lumbricoides reproductive tissues. Genetic Code Expansion To Enable Site-Specific Bioorthogonal Labeling of Functional G Protein-Coupled Receptors in Live Cells. Functional expression of oxytocin receptors in pulp-dentin complex. Ghrelin receptor signaling in health and disease: a biased view. Identification and expression analysis of G protein-coupled receptors in the cotton aphid, Aphis gossypii Glover. Structural and Molecular Insights into GPCR Function Global insights into the fine tuning of human A2AAR conformational dynamics in a ternary complex with an engineered G protein viewed by NMR. Fusarium graminearum Ste3 G-Protein Coupled Receptor: A Mediator of Hyphal Chemotropism and Pathogenesis. Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor. New insights into the structure and function of class B1 GPCRs. Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids. Tracking N- and C-termini of C. elegans polycystin-1 reveals their distinct targeting requirements and functions in cilia and extracellular vesicles. Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome: in silico protein structure analysis and molecular docking. Non-ionic cholesterol-based additives for the stabilization of membrane proteins. "Structural Clarity is Brought to Adhesion G protein Coupled Receptor Tethered Agonism". Surveying nonvisual arrestins reveals allosteric interactions between functional sites. Evaluating GPCR modeling and docking strategies in the era of deep learning-based protein structure prediction. Industry News Sosei Heptares and Neurocrine Biosciences won Out-Licensing Deal of the Year from Locust Walk Omass Therapeutics 2022 Review Sosei hooks millions from Eli Lilly alliance Septerna was selected as one of the Top Life Sciences Startups to Watch in 2023 by BioSpace Sosei Heptares Notes its Partner Tempero Bio has Received FDA Clearance to Advance Clinical Development of TMP-301 for Treatment of Alcohol and Substance Use Disorders AbbVie recruits a GPCR team in Oxford, buying out a fledgling biotech for $255M+ Domain Therapeutics announces first patient dosed with DT-9081 in phase I clinical study in patients with advanced, recurrent or metastatic solid tumors: the EPRAD study Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Hello Readers👋, We are working on bringing your the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for December 12 to December 18th, 2022. GPCR Activation and Signaling Molecular Mechanisms of PTH/PTHrP class B GPCR Signaling and Pharmacological Implications. GPCR Binders, Drugs, and more Persistent challenges in the development of an mGlu7 PAM in vivo tool compound: The discovery of VU6046980. Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic. GPCRs in Neuroscience Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain. GRK5 Deficiency in the Hippocampus Leads to Cognitive Impairment via Abnormal Microglial Alterations. GPCRs in Oncology and Immunology Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors. Methods & Updates in GPCR Research 3,4-Bis(hydroxymethyl)hexane-1,6-diol-based Maltosides (HDMs) for Membrane-Protein Study: Importance of Detergent Rigidity-Flexibility Balance in Protein Stability. iORbase: a database for the prediction of the structures and functions of insect olfactory receptors. GPCR Industry News Septerna Announces the Formation of a Cross-Functional Scientific and Drug Discovery Advisory Board Sosei Heptares and Lilly Enter Multi-target Collaboration and License Agreement in Diabetes and Metabolic Diseases Sosei Heptares Enters R&D Agreements with the University of Oxford and KU Leuven to Identify and Validate Key GPCRs Driving Gastrointestinal and Immune Disorders Inversago Pharma Doses First Patient in Phase 2 Trial of INV-202, an Oral, Peripherally-acting CB1 Inverse Agonist, in Patients with Diabetic Kidney Disease Chris Cargill, President and CEO, will present a company overview at the 41st Annual J.P. Morgan Healthcare Conference. Sosei Heptares' Partner Pfizer Progresses its Oral GLP-1 Receptor Agonist PF-07081532 into Phase 2 Clinical Trials for Treating Type 2 Diabetes and Obesity Special report 2022: Meet 20 women blazing trails in biopharma R&D ERNEST - 2022 Scientific Outputs Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023 Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. Deadline January 30, 2023. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Among the different families of G-protein-coupled receptors (GPCRs), adhesion GPCRs (aGPCRs) represent the second most abundant in humans. Structurally they characterize by a long extracellular region of adhesion-like domains which modulate protein-protein interactions; and also by the presence of the GPCR-Autoproteolysis INducing (GAIN) domain located upstream of the first transmembrane pass. As if its structure were not already complex enough, during their synthesis in the endoplasmic reticulum, many of these receptors are cleaved at the GPCR Proteolysis Site motif of the GAIN domain through an auto-catalysis process generating two peptides that are held together by non-covalent bonds during their transport to the membrane1. When I started studying aGPCRs, the structural conformation of the GAIN domain of ADGRL1/Lphn1 and ADGRB3/BAI3 was already known. These crystal structures showed how the Stalk region, which is a short peptide released from the GAIN during auto-proteolysis, has a β-lamin conformation and is held within the GAIN surrounded by numerous hydrophobic interactions1. However, at that time the structural conformation of the transmembrane (TM) region was not yet known. Fortunately, the scientific community has become increasingly interested in studying these proteins and this year the transmembrane structures of the aGPCRs ADGRL3/Lphn3, ADGRG1/GPR56, ADGRG5/GPR114, ADGRD1/GPR133, ADGRF1/GPR110, ADGRG2/GPR64, and ADGRG4/GPR112 were reported in their self-activating state, i.e. a unique activation model of aGPCRs where in the absence of the extracellular region the Stalk peptide functioning as an agonist (or also known as a tethered agonist) and adopts a hooked alpha-helix conformation within the transmembrane domains leading to receptor activation. The resolution of these Cryo-EM structures provided the basis for the mechanism of self-activation of aGPCRs supporting the encrypted ligand hypothesis that was put forward by the community before these structures were known2-6. As occurs with other GPCRs in an active state, in aGPCRs the rearrangements induced by the interaction of the Stalk sequence with the transmembrane regions promote their coupling with G-proteins. Different studies have shown that aGPCRs such as Lphns have promiscuous behavior, where in a constitutive state Lphns signal through different types of G proteins, so knowing the factors that determine the selectivity of coupling represents a very interesting area of research. Last month a very detailed paper analyzed the molecular mechanisms of the aGPCRs self-activation as well the selectivity of G-protein coupling using a mouse ADGRL3 receptor without extracellular region as a study model7. This paper proposes a series of molecular mechanisms that would be occurring during the self-activation of aGPCRs, some of which differ from those of GPCRs belonging other families, and I will tell you about some of their findings below. Through cell-based assays and Cryo-EM of high quality, it was possible to know that ADGRL3 can activate and form stable complexes with Gs, Gi, Gq, and G12, where like other GPCRs, the distal αH5 region of the G protein was needed to maintain an interface with the receptor core. Similar to Barros's 2022 report, which describes the Cryo-EM structure of human ADGRL3-G13, this paper reports that the stalk peptide of ADGRL3 adopts a hook conformation when binds to the binding pocket formed by TM1-3,5-7 and extracellular loop (ECL) 1,2,3. Furthermore, when an alignment analysis of the Stalk peptide of the aGPCR family was performed highlighted a new hydrophobic conserved motif composed of phenylalanine (F)/leucine (L) and methionine (M) which adopted a similar conformation in the ligand binding pocket and helps to stabilize the tethered ligand-receptor. Comparison between a predicted model of inactive receptor structure and self-activated Cryo-EM highlighted that outward movement of TM6 (a signature of GPCR activation), sharp bending of TM6, and tilting of TM7 and TM1 are characteristic of ADGRL3 self-activation. Interestingly, it was also reported that rearrangements of the TMs lead to a group of five hydrophobic amino acids present in TM1, 3, 5 and 7 forming a horizontal plane that helps to stabilize the self-active conformation of ADGRL3. Finally a comparative close analysis of the different Cryo-EM receptor structures with Gq, Gs, Gi and G12 showed that Gq/Gs have a similar mode of receptor binding, while Gi/G12 use a different engagement mechanism. Overall the count of interactions between the last eight αH5 residues of each G protein with the receptor showed that there are more polar interactions in Gq/Gs engagements than in G1/G12 engagements; where Gi had the fewest hydrophobic and polar interactions with the receptor and the αH5 tilt of G12 towards TM3/TM5 of the receptor is more pronounced compared to the rest of the G proteins. From a structural perspective, the -4 position of αH5 was key for the selectivity of G-protein coupling, since the change of amino acids in positions close to this position favored signaling toward a specific G-protein, which is interesting in biased signaling purposes. In view of the above, these new findings clearly demonstrate part of the molecular mechanisms involved in the self-activation of aGPCRs and open new perspectives for the community to formulate strategies to help modulate the activation and signaling of these receptors, particularly with a pharmacological approach. Indeed, despite their broad physiological importance in normal and pathological processes, so far no drugs have been approved that target any aGPCR. Check the original article at https://pubmed.ncbi.nlm.nih.gov/36309016/ Bibliography 1. Araç, D., et al., A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. Embo j, 2012. 31(6): p. 1364-78. 2. Barros-Álvarez, X., et al., The tethered peptide activation mechanism of adhesion GPCRs. Nature, 2022. 3. Ping, Y.-Q., et al., Structural basis for the tethered peptide activation of adhesion GPCRs. Nature, 2022. 4. Qu, X., et al., Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1. Nature, 2022. 5. Xiao, P., et al., Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature, 2022. 6. Boucard, A.A., Self-activated adhesion receptor proteins visualized. Nature, 2022. 604(7907): p. 628-630. 7. Qian, Y., Ma, Z., Liu, C., Li, X., Zhu, X., Wang, N., Xu, Z., Xia, R., Liang, J., Duan, Y., Yin, H., Xiong, Y., Zhang, A., Guo, C., Chen, Z., Huang, Z., & He, Y. (2022). Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling. Molecular cell, 82(22), 4340–4352.e6.

Hello Readers👋, Get the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for December 5 to December 11th, 2022. GPCR Activation and Signaling Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms, functions, and therapeutic targets Constitutive activity of the dopamine receptor D5R, highly expressed in CA1 hippocampal neurons, selectively reduces CaV 3.2 and CaV 3.3 currents GPCR Binders, Drugs, and more LP2, a cyclic angiotensin-(1-7) analog extended with an N-terminal D-lysine, impairs growth of patient-derived xenografts of colorectal carcinoma in mice Methods & Updates in GPCR Research Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor Reviews, GPCRs, and more Life, death and resurrection of plant GPCRs Structural and Molecular Insights into GPCR Function Synergistic and Competitive Lipid Interactions in the Serotonin 1A Receptor Microenvironment Industry News Addex and Indivior Extend Research Term Of Substance Use Disorder Gabab Positive Allosteric Modulator Discovery Collaboration Domain Therapeutics strengthens Scientific Advisory Board with appointment of immuno-oncology experts More millions roll in for Sosei Heptares Call for GPCR Papers GPCRs: Signal Transduction. Deadline February 12, 2023. Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. ERNEST GPCR early career investigator (ECI) Zoominar Survey 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Hello Readers👋, We are working on bringing your the latest GPCR News more frequently directly in your inbox and in the Ecosystem. Below is your Classified GPCR News at a glance for November 28 to December 4th, 2022. Adhesion GPCRs GPR56 C-terminal fragment mediates signal received by N-terminal fragment of another adhesion GPCR Latrophilin1 in neurons. GPCR Activation and Signaling Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers. FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury. Distal extracellular teneurin region (teneurin C-terminal associated peptide; TCAP) possesses independent intracellular calcium regulating actions, in vitro: A potential antagonist of corticotropin-releasing factor (CRF). Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity. Mechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signaling. Virtual screening yields refined GPCR agonists. GPCR Binders, Drugs, and more Altered signaling at the PTH receptor via modified agonist contacts with the extracellular domain provides a path to prolonged agonism in vivo. GPCRs in Cardiology, Endocrinology, and Taste Pathogenic variants of the GNAS gene introduce an abnormal amino acid sequence in the β6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families. Quantification of changes in human islet G protein-coupled receptor mRNA expression in obesity. Alterations in mouse visceral adipose tissue mRNA expression of islet G-protein-coupled receptor ligands in obesity. The Ca2+/CaM, Src kinase and/or PI3K-dependent EGFR transactivation via 5-HT2A and 5-HT1B receptor subtypes mediates 5-HT-induced vasoconstriction. GPCRs in Neuroscience CGRP physiology, pharmacology, and therapeutic targets: Migraine and beyond. Emerging approaches for decoding neuropeptide transmission. Exploring pharmacological inhibition of Gq/11 as an analgesic strategy. Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression. Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family. GPCRs in Oncology and Immunology Germinal Center-Related G Protein-Coupled Receptors in Antibody-Mediated Autoimmune Skin Diseases: from Basic Research to Clinical Trials. Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells. Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation. Methods & Updates in GPCR Research CPGL: Prediction of Compound-Protein Interaction by Integrating Graph Attention Network With Long Short-Term Memory Neural Network. Establishment of a CaCC-based Cell Model and Method for High-throughput Screening of M3 Receptor Drugs. High-performance optical control of GPCR signaling by bistable animal opsins MosOpn3 and LamPP in a molecular property-dependent manner. A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant. Genetically encoded tools for in vivo G-protein-coupled receptor agonist detection at cellular resolution. Reviews, GPCRs, and more The diversity of invertebrate visual opsins spanning Protostomia, Deuterostomia, and Cnidaria. Structural and Molecular Insights into GPCR Function Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin. Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1) and its interactions with antagonist and agonist ligands. Cryo-EM structure of G-protein-coupled receptor GPR17 in complex with inhibitory G protein. Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor. Molecular insights into the mechanism of sugar-modified enkephalin binding to opioid receptors. Oligomerization of the heteromeric γ-aminobutyric acid receptor GABAB in a eukaryotic cell-free system. Call for GPCR Papers GPCRs: Signal Transduction Advances in Computational and Chemical Methods to study GPCR Signal Transduction. Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery Summit | February 21-23, Boston. 2nd ERNEST Training School – February 20th to March 3rd. GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete. The Illuminating the Understudied Druggable Proteome Conference. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. June 11-16, 2023. 19th World Congress of Basic & Clinical Pharmacology 2023. July 2 - 7. Explore Dr. GPCR Ecosystem

Transmembrane domains of GPCR dimers – a novel hot spot for drug discovery G-protein-coupled receptors (GPCRs) can form biologically active homodimers or heterodimers which drive specific signaling pathways that can modulate both physiological and pathological functions. GPCR dimers are therefore emerging drug targets in different therapeutic areas including depression, hypertension, diabetes, and vascular dementia (A. Faron-Gorecka, et al. 2019). In this study Xin Cai et al. highlight the importance of GPCR dimers in drug discovery referring to important conformational changes, allosteric properties, ligand and functional selectivity. But what are the conformation changes that drive GPCR dimerization? The interaction between two receptors in a dimer involves a conformational change in the transmembrane domain (TMD), with the most compelling studies revealing that the transmembrane helices TM4 and TM5 on one hand, and TM1 and TM7 on the other hand, form possible dimerization interfaces (Ploier, B. et al. 2016; Dijkman, P. M. et al. 2018; Manglik, A. et al. 2012). Interestingly, the amplitude of the conformational changes due to ligand binding is limited at these interfaces. An important example of a GPCR forming both monomers and dimers with distinct functions in respect to ligand binding, receptor activation, desensitization and trafficking is the apelin receptor (APJ) (Y. Li, et al 2012; B. Bai, et al. 2014; B. Ji, et al. 2020; L. Wan, 2020). APJ receptors form both homodimers and heterodimers with other members of the class A GPCR family such as with bradykinin 1 and 2 receptors (B. Bai et al. 2014; B. Ji et al., 2020). GPCR dimers are very attractive molecular entities since they have been found to drive biased signalling. Various studies reported that the biased properties of ligands and receptors are a consequence of GPCR dimer formation, where the dimer corresponds to the biased receptor. Junke Liu et al. recently provided key insights into GPCR oligomerization and biased signalling, using PAFR as a model, showing that stabilization of PAFR oligomers promotes G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. How dynamic are GPCRs dimer interfaces? GPCRs constantly bind to form dimers and dissociate to form monomers. GPCRs dimers exist in a transient state however they are still able to be activated and interact with G proteins and therefore preserve their physiological functions, an important observation when considering them as potential targets. Different models of dimer formation have been described for different receptors such as the ‘rolling dimer’ interface model in which multiple dimer conformations co-exist and interconvert (P.M. Dijkman et al., 2018). Structural insights into metabotropic glutamate receptors have shown that the dimerization interface is affected by the activation state of the receptors, with the interface mainly located at TM4 and TM5 when mGluR2 dimers are inactive, switching to an interface mainly at TM6 when the receptor is active (L. Xue, et al. 2015). What is the potential of targeting GPCR dimer interface in drug discovery? GPCR drugs efficacy usually depends on a pathway (G protein or β-arrestin), whereas side effects are normally mediated by another pathway (I. Mantas et al. 2022). Therefore, the biased properties of GPCR dimers comprise an opportunity to boost efficacy while reducing side effects. But how can we target GPCR dimers? Recent studies found that peptides derived from the transmembrane region of GPCRs can block the formation of dimers and alter their function by destroying the interface between two receptors (M. Gallo et al. 2022). An example is a peptide derived from TM5/TM6 of the cannabinoid CB1 receptor (CB1R) which has been shown to alter the structure of CB1R–5HT2AR heterodimers, preventing cognitive impairment while preserving analgesia in vivo (M. Gallo et al. 2021). A more in-depth analysis of the functional specificity of transmembrane peptides will provide a better understanding of the physiopathological role of GPCRs dimerization while accelerating drug discovery targeting GPCR dimers. Check the original article at https://www.sciencedirect.com/science/article/pii/S1359644622004123?via%3Dihub #GPCR #DrGPCR#Ecosystem

Historically, ligands for GPCRs have been identified before their receptor counterparts. With the cloning revolution, several unidentified receptors have been found and were labelled as “orphan” for their endogenous ligands. Orphan GPCRs have been shown to play key roles in various physiological functions, such as sensory perception, reproduction, development, growth, metabolism, and are also linked to major diseases, such as neuroinflammatory, metabolic and autoimmune diseases. Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance in order to better understanding human physiology as well as to dissect the molecular mechanism governing the involvement of these receptors in human pathology. GPR84 is an example of an orphan GPCR (Sharman et al., 2011), although it is widely accepted that medium‐chain fatty acids (MCFAs) can bind to and activate this receptor with modest potency. GPR84 is a Gi‐coupled class A GPCR mainly expressed in immune cells and microglia in the brain (Wojciechowicz & Ma'ayan, 2020). GPR84 has been shown to be an attractive target in pro‐inflammatory conditions (Gagnon et al., 2018; Suzuki et al., 2013; Vermeire et al., 2017; Wojciechowicz & Ma'ayan, 2020) and efforts have been made to discover GPR84 antagonists. In this study Marsango et al. address two key questions in GPR84 biology and pharmacology: 1. how GPR84 expression profile correlates with physiological and pathological conditions? and 2. which ligands can be used as tool compounds to study the function and biology of this receptor? Regarding the first question, GPR84 overexpression in immune cells in a range of pro‐inflammatory disorders renders it a promising target in inflammatory and fibrotic conditions, including neuroinflammation (Audoy‐Remus et al., 2015), with ongoing clinical trials in idiopathic pulmonary fibrosis (Labéguère et al., 2014). GPR84 has been additionally proposed to be a potential biomarker in different inflammatory diseases (Arijs et al., 2011; Planell et al., 2017). Some studies have also reported GPR84 involvement in pain, atherosclerosis, and even metabolic disorders (Nicol et al., 2015, Audoy‐Remus et al., 2015, Du Toit et al., 2018). Regarding the second question, there is still a lot to be done in respect to tool compounds to study the function of this receptor towards clinical validation, as well as radiopharmaceuticals, including potential PET ligands, and suitable antibodies. Recent work has shown distinct functional outcomes of agonist ligands (Pillaiyar et al., 2018) with biased properties which can help to better elucidate the molecular pharmacology of this receptor. In addition, several GPR84 ligands have been described as well as GPR84 knockout mice. Among these ligands are orthosteric agonists such as alkylpyrimidine‐4,6‐diol derivatives (Liu et al., 2016; Zhang et al., 2016) and embelin (2,5‐dihydroxy‐3‐undecyl‐1,4‐benzoquinone) which is a natural product derived from the plant Embelia ribes (Gaidarov et al., 2018) which agonizes GPR84 but, interestingly, blocks the chemokine receptor CXCR2 and the adenosine A3 receptor (Gaidarov et al., 2018). IM (3,3′‐methylenebis‐1H‐indole) has been identified as a positive allosteric modulator of GPR84, a metabolite produced in vivo from indole‐3‐carbinol, which is present at high levels in some vegetables including broccoli and kale (Wang, Schoene, Milner, & Kim, 2012, Köse et al., 2020). GPR84 antagonists include a series of dihydropyrimidinoisoquinolinones (Labéguère et al., 2014), which behave as non‐competitive antagonists of GPR84 (Labéguère et al., 2020). From these series of compounds, GLPG1205 progressed into clinical development for the potential treatment of ulcerative colitis although it did not demonstrate sufficient efficacy (Labéguère et al., 2020). Overall, GPR84 is a promising target to exploit and the investment in better tools to study its function in both disease and physiological settings will likely potentiate drug discovery campaigns against this orphan GPCR. Check the original article at here! #GPCR #DrGPCR#Ecosystem

What is the molecular basis that determines that GPCRs bind selectively or promiscuously to different G proteins?. This question led Huang et al., 2022 to investigate the molecular basis involved in G protein-receptor interactions, particularly the differences between Gs and Gi/o coupling. Through Cryo-Electron Microscopy, authors reported the structures of four protein complexes integrated by a complete human serotonin receptor subtype and a dominant negative form of Gs or Gi: 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. Prior to this report we did not know how different serotonin receptor subtypes which share high sequence homology, coupled to different families of G proteins, so the comparison and structural analysis of these complexes revealed two important aspects: the specific residues involved in ligand selectivity and the interactions involved in the coupling of G proteins. The binding pockets for serotonin were virtually identical between the receptor-Gs and receptor-Gi complexes, suggesting that the selectivity of the G-protein lies in intrinsic features of the receptor rather than in a serotonin-induced mechanism. The discovery of the orthosteric binding pocket is of great importance in GPCRs field as it supports the development of alternatives to improve drug design to optimize receptor selectivity. In the same way, as in other GPCRs-G protein complexes, the structural analysis revealed that electrostatic interactions are crucial for the coupling of G-proteins to serotonin receptors. The structural differences found between the receptor-Gs and receptor-Gi complexes evidenced that 5-HT4/6/7-Gs coupled receptors have a cytosolic TM5 that is on average 5.7 residues longer and a TM6 that is 7.5 residues shorter compared to 5-HT1/4 receptors that couple to Gi/o. The TM5 extension of receptors Gs-coupled provides unique interactions that are not seen in complexes formed with Gi. These differences are mainly attributed to the characteristic Ras domain distance between Gs and Gi. Therefore the authors propose that the relative lengths of TM5 and TM6 in serotonin receptors function as a macro-switch to determine the selectivity of coupling between Gs or Gi/o. Additionally, structural analysis of the TM5 and TM6 regions of 27 class A GPCRs coupled to Gs or Gi/o yielded similar results, TM5 was 5.6 ± 1.5 residues longer while TM6 was 2.6 ± 1.6 residues shorter, concluding that the TM5-TM6 macro-switch length is conserved in class A GPCRs. Likewise, in this work the authors identify for the first time the specific amino acids that modulate the selectivity of coupling to Gs and Gi/o, reporting the presence of conserved residues for each type of G protein. The differences found at the residue level are referred to as micro-switches that will define a selective or promiscuous coupling of the receptor to the G protein. Interestingly, in the case of promiscuous receptors they found that these receptors shared conserved residues of both G protein families, suggesting that receptors that activate both Gs and Gi/o do so by combining the properties of the conserved residues with a mixture of Gs and Gi/o specific properties. These findings contribute to progress in understanding how serotonin receptors, one of the largest subfamilies of class A GPCRs and potential therapeutic targets that are activated by the same endogenous ligand, create a wide diversity of cellular responses. Check the original article at this link https://pubmed.ncbi.nlm.nih.gov/35714614/ *Above information was taken from the original article published by Huang et al., 2022. #GPCR #DrGPCR

Every year, with the month of October, comes the excitement of the Nobel session to the global scientific community. In the first few weeks of the month, the Royal Swedish Academy of Sciences and the Nobel Assembly at the Karolinska Institute announce the winners of the Nobel prizes in Physics, Chemistry, and Physiology or Medicine, the most recognizable awards for the impact of scientific work carried out by scientists in these three fields. This recognition also acknowledges the relative importance of a particular scientific area received from the scientific community and the perceived impact the finding has had on human scientific progress. Therefore, the presentation of 10 or more Nobel prizes highlights the importance of research work on the GPCR-mediated signal transduction garnered in the human scientific enterprise. The first Nobel prize that can be attributed to work related to GPCR-mediated signaling was the 1947 Nobel Prize in Physiology or Medicine, awarded to Carl Ferdinand Cori, Gerty Theresa Cori (née Radnitz), and Bernardo Alberto Houssay for their discoveries related to how glycogen is broken down to glucose and resynthesized in the body for use as a store and source of energy. Through their Nobel prize-winning work, the Coris found that adrenaline, a nonselective agonist for all types of adrenergic receptors, decreases the amount of glycogen in the liver and muscles. [1-6] Houssay received this honor for his discoveries concerning the role of the various hormones, including adrenaline secreted from the anterior pituitary lobe, in carbohydrate metabolism and the onset of diabetes. In 1967, the Nobel Prize in Physiology or Medicine was awarded jointly to Ragnar Arthur Granit, Haldan Keffer Hartline, and George David Wald for their discoveries concerning the primary physiological and chemical visual processes in the eye.[7–11] Through Nobel prize-winning research work, Wald made important discoveries on the role that the class-A archetypical GPCR rhodopsin plays in scoptic vision and night blindness. In 1970, the Nobel Prize in Physiology or Medicine was awarded to Julius Axelrod, Bernard Katz, and Ulf Svante von Euler for their work on the release and reuptake of neurotransmitters in neural communication.[12–17] Katz's scientific studies involved the release of the neurotransmitter acetylcholine, whereas the studies by Axelrod and von Euler focused on the neurotransmitter norepinephrine. Norepinephrine exerts its effects by binding to α- and β-adrenergic receptors, while acetylcholine binds to nicotinic acetylcholine receptors and muscarinic acetylcholine receptors.[18] The 1971 Nobel Prize in Physiology or Medicine went to Earl Wilbur Sutherland Jr for discovering the key role of adenylate cyclase, which produces the archetypical secondary messenger cyclic AMP (cAMP), plays in cellular signaling.[20,21] Adenylate cyclase is a major component of the downstream signaling cascade of the cAMP signal pathway, one of the two principal signal transduction pathways associated with GPCRs mediated signaling.[19–23] The 1988 Nobel Prize in Physiology or Medicine went to George Herbert Hitchings, Sir James Whyte Black, and Gertrude Belle Elion for their discoveries of important principles for drug treatment.[24–30] Black was particularly interested in developing drugs that targeted GPCRs and was credited with discovering propranolol, an antagonist for ß-adrenergic receptors, and cimetidine, an antagonist for histamine H2 receptor.[31,32] The 1992 Nobel Prize in Physiology or Medicine was awarded to Edwin Gerhard Krebs and Edmond Henri Fischer for describing how reversible phosphorylation works as a switch to activate proteins and to regulate various cellular processes, including glycogenolysis.[33–39] In their work, the duo further investigated the work of Gerty Cori and Carl Cori on carbohydrate metabolism. Incidentally, phosphorylation is a key regulatory mechanism employed in the GPCR-mediated signal transduction, where signaling of most GPCRs via the G-protein-dependent pathway is terminated by the phosphorylation of active receptors by specific kinases. Moreover, the G protein-independent pathway is mainly regulated by arrestin, which recognizes and binds phosphorylated GPCRs. The 1994 Nobel Prize in Physiology or Medicine was awarded to Alfred Goodman Gilman and Martin Rodbell for their discovery of G-proteins and the role of these proteins in signal transduction in cells.[40–46] In his work, Rodbell demonstrated that signal transduction through the cell membrane involves a cooperative action of three different functional entities: (1) a discriminator or receptor, which binds the primary messenger, (2) a transducer that requires GTP, and (3) an amplifier that generates large quantities of a second messenger. Gilman discovered that the transducer component of signal transduction that requires GTP is G-protein and was the first to isolate it through his work on leukemia cells. G protein-dependent signaling is the most well-known mechanism employed in GPCRs mediated signal transduction.[47] The 2000 Nobel Prize in Physiology or Medicine went to Eric Richard Kandel, Arvid Carlsson, and Paul Greengard for research on signal transduction in the nervous system.[48–54] Carlsson won the prize for his discovery that dopamine is a neurotransmitter produced in the basal ganglia, a brain region involved in movement control. Dopamine exerts its action in the human nervous system via dopamine receptors and human trace amine-associated receptor 1 (hTAAR1). Greengard was recognized for his contributions to the elucidation of the signaling pathways by which neurotransmitters such as dopamine, noradrenaline, and serotonin control neuronal excitability.[55,56] He identified a number of signal transduction proteins, particularly kinases and phosphatases, that are involved in synaptic transmission[55,56] Kandel was honored for demonstrating that cellular signaling events such as ion channel conduction and synaptic neurotransmitter release are involved in "short-term memory", whereas cAMP signaling and new protein synthesis are required for "long-term memory". The 2004 Nobel Prize in Physiology or Medicine went to Richard Axel and Linda Brown Buck for their work on Class-A olfactory receptors.[57–61] The two jointly carried out work to discover that sensing smell involved a large number of relatively specific olfactory receptors that are structurally similar to rhodopsin. These odorant receptors (ORs) now account for about 60% of all identified human GPCRs. The most recent Nobel prize awarded for work relevant to GPCR-mediated signaling was the 2012 Nobel Prize in Chemistry to Brian Kent Kobilka and Robert Joseph Lefkowitz for their work on GPCR function.[62–66] Lefkowitz was able to isolate β-adrenergic receptors from tissue samples to carry out the first structure-function characterization studies on GPCRs. Later on, Kobilka joined in with Lefkowitz to identify the shared architecture of the β-adrenergic receptor with that of rhodopsin.[67] In 2011, Kobilka further contributed to the field by obtaining the first X-ray crystal structure of a GPCR bound to its signaling partner (β-adrenergic receptor bound to the partial inverse agonist carazolol).[67] In spite of these advancements, there is much more to be discovered regarding how GPCRs mediate signaling. Our understanding of how various factors, such as lipid composition, osmotic stress, and allosteric ligands, modulate the conformational dynamics of GPCRs remains crude. Much more need to be uncovered about bias signaling, tissue-specific GPCR activation profiles, compartmentalized GPCR signaling, and location bias.[68–70] Further, our understanding of cross-talk between GPCR-mediated signaling pathways with other cellular signaling pathways, as well as non-signaling roles of GPCRs, such as acting as transcription factors, are still in their infancy. Therefore, we envision that this field will continue to produce high-impact research work that will garner more accolades from the global scientific community and continue to make large scientific discoveries to the improvement of human well-being.[68–72] References: 1. The Nobel Prize in Physiology or Medicine 1947. https://www.nobelprize.org/prizes/medicine/1947/summary/. 2. Bernardo Houssay – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1947/houssay/facts/. 3. Carl Cori – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1947/cori-cf/facts/. 4. Gerty Cori - Facts. https://www.nobelprize.org/prizes/medicine/1947/cori-gt/facts/. 5. Nobel Prize for Physiology and Medicine, 1947: Prof. Carl F. Cori and Mrs. Cori. Nature 160, 599–599 (1947). https://doi.org/10.1038/160599c0/. 6. Physiology or Medicine 1947 - Presentation Speech - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1947/ceremony-speech/. 7. Keffer Hartline - Biographical. https://www.nobelprize.org/prizes/medicine/1967/hartline/biographical/. 8. Dowling, J. E. Nobel Prize: Three Named for Medicine, Physiology Award. Science (1979) 158, 468–469 (1967). https://doi.org/10.1126/SCIENCE.158.3800.468/. 9. Ragnar Granit – Nobel Lecture - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1967/granit/lecture/. 10. George Wald – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1967/wald/facts/. 11. The Nobel Prize in Physiology or Medicine 1967 - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1967/summary/. 12. Julius Axelrod – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/axelrod/facts/. 13. Ulf von Euler – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/euler/facts/. 14. Sir Bernard Katz – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/katz/facts/. 15. Award ceremony speech - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/ceremony-speech/. 16. The Nobel Prize in Physiology or Medicine 1970 - Speed read: Passing the Message On - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/speedread/. 17. The Nobel Prize in Physiology or Medicine 1970 - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1970/summary/. 18. Shampo, M. A. & Kyle, R. A. Sir Bernard Katz--winner of Nobel Prize in physiology or medicine. Mayo Clinic proceedings. Mayo Clinic 68, 262 (1993). https://doi.org/10.1016/S0025-6196(12)60046-9/. 19. Physiology or Medicine 1971 - Press release - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1971/press-release/. 20. The Nobel Prize in Physiology or Medicine 1971 - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1971/summary/. 21. Earl W. Sutherland, Jr. – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1971/sutherland/facts/. 22. Earl W. Sutherland, Jr. – Banquet speech - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1971/sutherland/speech/. 23. Earl W. Sutherland, Jr. – Nobel Lecture - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1971/sutherland/lecture/. 24. George H. Hitchings – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/hitchings/facts/. 25. Sir James W. 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November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

September 2022 "Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying mutations vary considerably. In this work, we utilize deep mutational scanning to quantitatively compare the plasma membrane expression of 123 known pathogenic rhodopsin variants in the presence and absence of the stabilizing cofactor 9-cis-retinal. We identify 69 retinopathy variants, including 20 previously uncharacterized variants, that exhibit diminished plasma membrane expression in HEK293T cells. Of these apparent class II variants, 67 exhibit a measurable increase in expression in the presence of 9-cis-retinal. However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations. Evaluation of the observed shifts relative to thermodynamic estimates for the coupling between binding and folding suggests underlying differences in stability constrains the magnitude of their response to retinal. Nevertheless, estimates from computational modeling suggest that many of the least sensitive variants also directly compromise binding. Finally, we evaluate the functional properties of three previous uncharacterized, retinal-sensitive variants (ΔN73, S131P, and R135G) and show that two of these retain residual function in vitro. Together, our results provide a comprehensive experimental characterization of the proteostatic properties of retinopathy variants and their response to retinal." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

September 2022 "Opsins allow us to see. They are G-protein-coupled receptors and bind as ligand retinal, which is bound covalently to a lysine in the seventh transmembrane domain. This makes opsins light-sensitive. The lysine is so conserved that it is used to define a sequence as an opsin and thus phylogenetic opsin reconstructions discard any sequence without it. However, recently, opsins were found that function not only as photoreceptors but also as chemoreceptors. For chemoreception, the lysine is not needed. Therefore, we wondered: Do opsins exists that have lost this lysine during evolution? To find such opsins, we built an automatic pipeline for reconstructing a large-scale opsin phylogeny. The pipeline compiles and aligns sequences from public sources, reconstructs the phylogeny, prunes rogue sequences, and visualizes the resulting tree. Our final opsin phylogeny is the largest to date with 4956 opsins. Among them is a clade of 33 opsins that have the lysine replaced by glutamic acid. Thus, we call them gluopsins. The gluopsins are mainly dragonfly and butterfly opsins, closely related to the RGR-opsins and the retinochromes. Like those, they have a derived NPxxY motif. However, what their particular function is, remains to be seen." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

October 2022 "Enzymatic and cellular signalling biosensors are used to decipher the activities of complex biological systems. Biosensors for monitoring G protein-coupled receptors (GPCRs), the most drugged class of proteins in the human body, are plentiful and vary in utility, form and function. Their applications have continually expanded our understanding of this important protein class. Here, we briefly summarize a subset of this field with accelerating importance: transducer biosensors measuring receptor-coupling and selectivity, with an emphasis on sensors measuring receptor association and activation of heterotrimeric signalling complexes." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

October 2022 Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. " Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

October 2022 GPR125 (ADGRA3) is an autocleavable adhesion GPCR that traffics with Dlg1 to the basolateral membrane and regulates epithelial apicobasal polarity "The adhesion family of G protein-coupled receptors (GPCRs) is defined by an N-terminal large extracellular region that contains various adhesion-related domains and a highly-conserved GPCR-autoproteolysis-inducing (GAIN) domain, the latter of which is located immediately before a canonical seven-transmembrane domain. These receptors are expressed widely and involved in various functions including development, angiogenesis, synapse formation, and tumorigenesis. GPR125 (ADGRA3), an orphan adhesion GPCR, has been shown to modulate planar cell polarity in gastrulating zebrafish, but its biochemical properties and role in mammalian cells have remained largely unknown. Here, we show that human GPR125 likely undergoes cis-autoproteolysis when expressed in canine kidney epithelial MDCK cells and human embryonic kidney HEK293 cells. The cleavage appears to occur at an atypical GPCR proteolysis site within the GAIN domain during an early stage of receptor biosynthesis. The products, i.e., the N-terminal and C-terminal fragments, seem to remain associated after self-proteolysis, as observed in other adhesion GPCRs. Furthermore, in polarized MDCK cells, GPR125 is exclusively recruited to the basolateral domain of the plasma membrane. The recruitment likely requires the C-terminal PDZ-domain-binding motif of GPR125 and its interaction with the cell polarity protein Dlg1. Knockdown of GPR125 as well as that of Dlg1 results in formation of aberrant cysts with multiple lumens in Matrigel 3D culture of MDCK cells. Consistent with the multilumen phenotype, mitotic spindles are incorrectly oriented during cystogenesis in GPR125-KO MDCK cells. Thus, the basolateral protein GPR125, an autocleavable adhesion GPCR, appears to play a crucial role in apicobasal polarization in epithelial cells." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the newsletter HERE

November 2022 "Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. The mGlu5 receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu5 receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu5 receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment- (1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu5 identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 μM, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu5 signaling in functional assays. The results demonstrate that virtual screens of fragment- and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

November 2022 "Adhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with Gq, Gs, Gi, and G12. The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G12 coupling. A comparison of Gq, Gs, Gi, and G12 engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of αH5 of Gα. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

November 2022 "Dimerization of beta 2-adrenergic receptor (β2-AR) has been observed across various physiologies. However, the function of dimeric β2-AR is still elusive. Here, we revealed that dimerization of β2-AR is responsible for the constitutive activity of β2-AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient β2-AR dimers exist in a resting state, and the dimer was disrupted by the inverse agonists. A Gαs preferentially interacts with dimeric β2-AR, but not monomeric β2-AR, in a resting state, resulting in the production of a resting cAMP level. The formation of β2-AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric β2-AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of β2-AR. Our model not only shows the function of dimeric β2-AR but also provides a molecular insight into the mechanism of the inverse agonism of β2-AR." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

November 2022 "Despite the growing number of G protein-coupled receptor (GPCR) structures, only 39 structures have been cocrystallized with allosteric inhibitors. These structures have been studied by protein mapping using the FTMap server, which determines the clustering of small organic probe molecules distributed on the protein surface. The method has found druggable sites overlapping with the cocrystallized allosteric ligands in 21 GPCR structures. Mapping of Alphafold2 generated models of these proteins confirms that the same sites can be identified without the presence of bound ligands. We then mapped the 394 GPCR X-ray structures available at the time of the analysis (September 2020). Results show that for each of the 21 structures with bound ligands there exist many other GPCRs that have a strong binding hot spot at the same location, suggesting potential allosteric sites in a large variety of GPCRs. These sites cluster at nine distinct locations, and each can be found in many different proteins. However, ligands binding at the same location generally show little or no similarity, and the amino acid residues interacting with these ligands also differ. Results confirm the possibility of specifically targeting these sites across GPCRs for allosteric modulation and help to identify the most likely binding sites among the limited number of potential locations." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

November 2022 "Neuropeptides produce robust effects on behavior across species, and recent research has benefited from advances in high-resolution techniques to investigate peptidergic transmission and expression throughout the brain in model systems. Neuropeptides exhibit distinct characteristics which includes their post-translational processing, release from dense core vesicles, and ability to activate G-protein-coupled receptors (GPCRs). These complex properties have driven the need for development of specialized tools that can sense neuropeptide expression, cell activity, and release. Current research has focused on isolating when and how neuropeptide transmission occurs, as well as the conditions in which neuropeptides directly mediate physiological and adaptive behavioral states. Here we describe the current technological landscape in which the field is operating to decode key questions regarding these dynamic neuromodulators." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

November 2022 Deciphering the signaling mechanisms of β-arrestin1 and β-arrestin2 in regulation of cancer cell cycle and metastasis "β-Arrestins are ubiquitously expressed intracellular proteins with many functions which interact directly and indirectly with a wide number of cellular partners and mediate downstream signaling. Originally, β-arrestins were identified for their contribution to GPCR desensitization to agonist-mediated activation, followed by receptor endocytosis and ubiquitylation. However, current investigations have now recognized that in addition to GPCR arresting (hence the name arrestin). β-Arrestins are adaptor proteins that control the recruitment, activation, and scaffolding of numerous cytoplasmic signaling complexes and assist in G-protein receptor signaling, thus bringing them into close proximity. They have participated in various cellular processes such as cell proliferation, migration, apoptosis, and transcription via canonical and noncanonical pathways. Despite their significant recognition in several physiological processes, these activities are also involved in the onset and progression of various cancers. This review delivers a concise overview of the role of β-arrestins with a primary emphasis on the signaling processes which underlie the mechanism of β-arrestins in the onset of cancer. Understanding these processes has important implications for understanding the therapeutic intervention and treatment of cancer in the future." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

October 2022 β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells "β-arrestins mediate regulatory processes for over 800 different G protein-coupled receptors (GPCRs) by adopting specific conformations that result from the geometry of the GPCR-β-arrestin complex. However, whether β-arrestin1 and 2 respond differently for binding to the same GPCR is still unknown. Employing GRK knockout cells and β-arrestins lacking the finger-loop-region, we show that the two isoforms prefer to associate with the active parathyroid hormone 1 receptor (PTH1R) in different complex configurations ("hanging" and "core"). Furthermore, the utilisation of advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when bound to active PTH1R (P-R*). Moreover, we assess β-arrestin conformational changes that are induced specifically by proximal and distal C-terminal phosphorylation and in the absence of GPCR kinases (GRKs) (R*). Here, we show differences between conformational changes that are induced by P-R* or R* receptor states and further disclose the impact of site-specific GPCR phosphorylation on arrestin-coupling and function." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter

September 2022 "Sound is converted by hair cells in the cochlea into electrical signals, which are transmitted by spiral ganglion neurons (SGNs) and heard by the auditory cortex. G protein-coupled receptors (GPCRs) are crucial receptors that regulate a wide range of physiological functions in different organ and tissues. The research of GPCRs in the cochlea is essential for the understanding of the cochlea development, hearing disorders, and the treatment for hearing loss. Recently, several GPCRs have been found to play important roles in the cochlea. Frizzleds and Lgrs are dominant GPCRs that regulate stem cell self-renew abilities. Moreover, Frizzleds and Celsrs have been demonstrated to play core roles in the modulation of cochlear planar cell polarity (PCP). In addition, hearing loss can be caused by mutations of certain GPCRs, such as Vlgr1, Gpr156, S1P2, and Gpr126. And A1, A2A, and CB2 activation by agonists has protective functions on noise- or drug-induced hearing loss. Here, we review the key findings of GPCR in the cochlea and discuss the role of GPCR in the cochlea, such as stem cell fate, PCP, hearing loss, and hearing protection." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter

October 2022 Dimerization of β2-adrenergic receptor is responsible for the constitutive activity subjected to inverse agonism "Dimerization of beta 2-adrenergic receptor (β2-AR) has been observed across various physiologies. However, the function of dimeric β2-AR is still elusive. Here, we revealed that dimerization of β2-AR is responsible for the constitutive activity of β2-AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient β2-AR dimers exist in a resting state, and the dimer was disrupted by the inverse agonists. A Gαs preferentially interacts with dimeric β2-AR, but not monomeric β2-AR, in a resting state, resulting in the production of a resting cAMP level. The formation of β2-AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric β2-AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of β2-AR. Our model not only shows the function of dimeric β2-AR but also provides a molecular insight into the mechanism of the inverse agonism of β2-AR." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter