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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. Black – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/black/facts/. 26. Gertrude B. Elion – Facts - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/elion/facts/. 27. Sir James W. Black – Nobel Lecture - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/black/lecture/. 28. Award ceremony speech - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/ceremony-speech/. 29. Gertrude B. Elion – Nobel Lecture - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/elion/lecture/. 30. The Nobel Prize in Physiology or Medicine 1988 - NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1988/summary/. 31. McGrath, J. C. & Bond, R. A. Sir James Whyte Black OM. 14 June 192422 March 2010. BIOGRAPHICAL MEMOIRS OF FELLOWS OF THE ROYAL SOCIETY 70, 23–40 (2021). https://royalsocietypublishing.org/doi/10.1098/rsbm.2019.0047/. 32. Ekaterini Tiligada, C., Tiligada, E. & Ennis, M. 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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 "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

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 "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 "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

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

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors "Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo-electron microscopy structures of CX3CR1-Gi1 complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-Gi complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling and provide insights into the diversity of G protein coupling." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "Pregnant and lactating women have been discouraged from using cannabis by Health Canada. However, the increasing rate of cannabis use among pregnant women has presented an urgent need to investigate its physiological effects during the perinatal period. During pregnancy, the mammary gland (MG) undergoes remodeling, which involves alveolar differentiation of mammary epithelial cells (MECs), which is essential for breast milk production and secretion. Limited evidence has been reported on the impact of cannabis or its components, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on MG development or MEC differentiation. In this study, we investigated the effects of THC and CBD on the differentiation of MECs by assessing changes in cellular viability, lipid accumulation, and gene and protein expression of major milk protein and lipid synthesizing markers. using the HC11 cells as a model. We hypothesized that THC and CBD will negatively impact the synthesis of milk proteins and lipids, as well as lipid markers in HC11 cells. Our results demonstrated that THC and CBD reduced cellular viability at concentrations above 30μM and 20μM, respectively. Relative to control, 10μM THC and 10μM CBD reduced mRNA levels of milk proteins (CSN2 and WAP), lipid synthesizing and glucose transport markers (GLUT 1, HK2, FASN, FABP4, PLIN2 and LPL), as well as whey acidic protein and lipid levels. In addition, co-treatment of a CB2 antagonist with THC, and a CB2 agonist with CBD, reversed the impact of THC and CBD on the mRNA levels of key markers, respectively. In conclusion, 10μM THC and CBD altered the differentiation of HC11 cells, in part via the CB2 receptor." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 High hedgehog signaling is transduced by a multikinase-dependent switch controlling the apico-basal distribution of the GPCR smoothened "The oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO) is a key transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures. Here, we examine how HH controls SMO subcellular localization and activity in a polarized epithelium using the Drosophila wing imaginal disc as a model. We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase. Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of HH to the apico-basal distribution of SMO and provide a novel mechanism for the regulation of a GPCR." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Arrestins interact with G protein-coupled receptors (GPCRs) to stop G protein activation and to initiate key signaling pathways. Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling, but whether this process is conserved among GPCRs is poorly understood. Here, we report the cryo-electron microscopy active structure of the wild-type arginine-vasopressin V2 receptor (V2R) in complex with β-arrestin1. It reveals an atypical position of β-arrestin1 compared to previously described GPCR-arrestin assemblies, associated with an original V2R/β-arrestin1 interface involving all receptor intracellular loops. Phosphorylated sites of the V2R carboxyl terminus are clearly identified and interact extensively with the β-arrestin1 N-lobe, in agreement with structural data obtained with chimeric or synthetic systems. Overall, these findings highlight a notable structural variability among GPCR-arrestin signaling complexes." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling "Aims: Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause G protein dysregulation, contributing to modest blood pressure elevation and exaggerated cardiac hypertrophic response to pressure-overload. Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is unknown. Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac structure and function." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "G protein-coupled receptors (GPCRs) are important drug targets characterized by a canonical seven transmembrane (TM) helix architecture. Recent advances in X-ray crystallography and cryo-EM have resulted in a wealth of GPCR structures that have been used in drug design and formed the basis for mechanistic activation hypotheses. Here, ensemble refinement (ER) of crystallographic structures is applied to explore the impact of binding of agonists and antagonist/inverse agonists to selected structures of cannabinoid receptor 1 (CB1R), β2 adrenergic receptor (β2 AR) and A2A adenosine receptor (A2A AR). " Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Increased Anxiety-like Behaviors in Adgra1-/- Male But Not Female Mice are Attributable to Elevated Neuron Dendrite Density, Upregulated PSD95 Expression, and Abnormal Activation of the PI3K/AKT/GSK-3β and MEK/ERK Pathways "Adhesion G protein-coupled receptor A1 (ADGRA1) belongs to the G protein-coupled receptor (GPCR) family, and its physiological function remains largely unknown. We found that Adgra1 is highly and exclusively expressed in the brain, suggesting that Adgra1 may be involved in the regulation of neurological behaviors including anxiety, depression, learning and memory. To this end, we comprehensively analyzed the potential role of ADGRA1 in the neurobehaviors of mice by comparing Adgra1-/- and their wild-type (wt) littermates. We found that Adgra1-/- male but not female mice exhibited elevated anxiety levels in the open field, elevated plus maze, and light-dark box tests, with normal depression levels in the tail-suspension and forced-swim tests, and comparable learning and memory abilities in the Morris water maze, Y maze, fear condition, and step-down avoidance tests. Further studies showed that ADGRA1 deficiency resulted in higher dendritic branching complexity and spine density as evidenced by elevated expression levels of SYN and PSD95 in amygdalae of male mice. Finally, we found that PI3K/AKT/GSK-3β and MEK/ERK in amygdalae of Adgra1-deficient male mice were aberrantly activated when compared to wt male mice. Together, our findings reveal an important suppressive role of ADGRA1 in anxiety control and synaptic function by regulating the PI3K/AKT/GSK-3β and MEK/ERK pathways in amygdalae of male mice, implicating a potential, therapeutic application in novel anti-anxiety drug development." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Visual phototransduction is the most extensively studied G protein-coupled receptor (GPCR) signaling pathway because of its quantifiable stimulus, non-redundancy of genes, and immense importance in vision. We summarize recent discoveries that have advanced our understanding of rod outer segment (ROS) morphology and the pathological basis of retinal diseases. We have combined recently published cryo-electron tomography (cryo-ET) data on the ROS with structural knowledge on individual proteins to define the precise spatial limitations under which phototransduction occurs. Although hypothetical, the reconstruction of the rod phototransduction system highlights the potential roles of phosphodiesterase 6 (PDE6) and guanylate cyclases (GCs) in maintaining the spacing between ROS discs, suggesting a plausible mechanism by which intrinsic optical signals are generated in the retina." Read more at the source #DrGPCR #GPCR #IndustryNews