- Opioid signaling and design of analgesics. [Journal Article]Prog Mol Biol Transl Sci. 2023; 195:153-176.PM
- Clinical treatment of acute to severe pain relies on the use of opioids. While their potency is significant, there are considerable side effects that can negatively affect patients. Their rise in usage has correlated with the current opioid epidemic in the United States, which has led to more than 70,000 deaths per year (Volkow and Blanco, 2021). Opioid-related drug development aims to make targe…
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- Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice. [Journal Article]Front Cell Dev Biol. 2022; 10:1092161.FC
- In the brain, primary cilia are found on most, if not all, central neurons. The importance of neuronal cilia is underscored by the fact that human diseases caused by primary cilia dysfunction, which are known as ciliopathies, are associated with neuropathologies, including neuropsychiatric disorders and learning and memory deficits. Neuronal cilia are enriched for certain G protein-coupled recept…
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- Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor. [Journal Article]
- The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiol…
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- Exercise may alleviate age-related spatial memory impairment by rescuing β-adrenergic receptor dysregulation via both G protein-dependent and β-arrestin-dependent mechanisms in rat hippocampus. [Journal Article]Brain Res. 2023 Jan 20; 1804:148250.BR
- Hippocampal-dependent memory abilities including spatial memory decline with age. Exercise improves memory decline in aging brain, but, the precise mechanisms are still unknown. Learning and memory are recently hypothesized to be mediated by a β-arrestin (βArr)-dependent β-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of β-adrenergic …
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- Biased GLP-2 agonist with strong G protein-coupling but impaired arrestin recruitment and receptor desensitization enhances intestinal growth in mice. [Journal Article]Br J Pharmacol. 2023 Jan 22 [Online ahead of print]BJ
- CONCLUSIONS: G protein-biased GLP-2R agonists with diminished receptor desensitization have superior intestinotrophic effect and could represent improved treatment of intestinal insufficiency including SBS.
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- Improved Split TEV GPCR β-arrestin-2 Recruitment Assays via Systematic Analysis of Signal Peptide and β-arrestin Binding Motif Variants. [Journal Article]
- G protein-coupled receptors (GPCRs) are major disease-relevant drug targets; robust monitoring of their activities upon drug treatment is key to drug discovery. The split TEV cell-based assay technique monitors the interaction of an activated GPCR with β-arrestin-2 through TEV protein fragment complementation using a luminescent signal as the readout. In this work, split TEV GPCR β-arrestin-2 rec…
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- Cannabinoid tolerance in S426A/S430A x beta-arrestin 2 knock-out double mutant mice. [Journal Article]J Pharmacol Exp Ther. 2023 Jan 20 [Online ahead of print]JP
- Tolerance to compounds that target G protein-coupled receptors (GPCR), such as the cannabinoid type-1 receptor (CB1R), is in part facilitated by receptor desensitization. Processes that mediate CB1R desensitization include phosphorylation of CB1R residues S426 and S430 by a GPCR kinase (GRK), and subsequent recruitment of the b-arrestin2 scaffolding protein. Tolerance to cannabinoid drugs is redu…
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- DPP4-Truncated CXCL12 Alters CXCR4/ACKR3 Signaling, Osteogenic Cell Differentiation, Migration, and Senescence. [Journal Article]
- Bone marrow skeletal stem cells (SSCs) secrete many cytokines including stromal derived factor-1 or CXCL12, which influences cell proliferation, migration, and differentiation. All CXCL12 splice variants are rapidly truncated on their N-terminus by dipeptidyl peptidase 4 (DPP4). This includes the common variant CXCL12 alpha (1-68) releasing a much less studied metabolite CXCL12(3-68). Here, we fo…
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- Sequestration of Gβγ by deubiquitinated arrestins into the nucleus as a novel desensitization mechanism of G protein-coupled receptors. [Journal Article]
- CONCLUSIONS: In addition to the conventional mechanism of desensitization, which occurs on the plasma membrane and in the cytosol, this study provides a new insight that another desensitization pathway in which nuclear trafficking plays a critical role is operating. It is plausible that multiple, complementary desensitization measures are in place to properly induce desensitization depending on receptor characteristics or the surrounding environment. Video Abstract.
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- Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship. [Journal Article]
- GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high…
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- In vitro characterization of the pyrazole-carrying synthetic cannabinoid receptor agonist 5F-3,5-AB-PFUPPYCA and its structural analogs. [Journal Article]Forensic Sci Int. 2023 Jan 10; 343:111565.FS
- The synthetic cannabinoid receptor agonist (SCRA) market is undergoing important changes since the enactment of the 2021 class-wide generic SCRA ban in China, one of the most important source countries for new psychoactive substances (NPS). Recently, various compounds with new structural features, synthesized to bypass this legislation, have entered the recreational drug market. Certain monocycli…
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- Comparative evaluation of biased agonists Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II (SD Ang II) and Sarcosine1 , Isoleucine8 -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors. [Journal Article]
- Angiotensin II analogue and β-arrestin biased agonist TRV027 (Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the β-arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by …
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- Initial pharmacological characterization of a major hydroxy metabolite of PF-5190457: inverse agonist activity of PF-6870961 at the ghrelin receptor. [Journal Article]J Pharmacol Exp Ther. 2023 Jan 11 [Online ahead of print]JP
- Preclinical and clinical studies have identified the ghrelin receptor (growth hormone secretagogue receptor 1a; GHSR1a) as a potential target for treating alcohol use disorder. A recent Phase 1a clinical trial of a GHSR1a antagonist/inverse agonist, PF-5190457, in individuals with heavy alcohol drinking, identified a previously undetected major hydroxy metabolite of PF-5190457, namely PF-6870961.…
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- New simulation insights on the structural transition mechanism of bovine rhodopsin activation. [Journal Article]Proteins. 2023 Jan 11 [Online ahead of print]P
- Inactive rhodopsin can absorb photons, which induces different structural transitions that finally activate rhodopsin. We have examined the change in spatial configurations and physicochemical factors that result during the transition mechanism from the inactive to the active rhodopsin state via intermediates. During the activation process, many existing atomic contacts are disrupted, and new one…
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- Using canavanine resistance to measure mutation rates in Schizosaccharomyces pombe. [Journal Article]
- We constructed a panel of S. pombe strains expressing DNA polymerase ε variants associated with cancer, specifically POLES297F, POLEV411L, POLEL424V, POLES459F, and used these to compare mutation rates determined by canavanine resistance with other selective methods. Canavanine-resistance mutation rates are broadly similar to those seen with reversion of the ade-485 mutation to adenine prototroph…
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- Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists. [Journal Article]
- Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible sc…
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- Brusatol suppresses the tumor growth and metastasis of colorectal cancer via upregulating ARRDC4 expression through modulating PI3K/YAP1/TAZ Pathway. [Journal Article]Phytomedicine. 2023 Jan; 109:154567.P
- CONCLUSIONS: This study reported for the first time that BR is a potent ARRDC4 agonist, and is worthy of further development into a new therapeutic strategy for CRC.
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- Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling. [Journal Article]Mol Psychiatry. 2023 Jan 06 [Online ahead of print]MP
- Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system i…
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- [β-arrestin2 recruitment by β-adrenergic receptor agonists and antagonists]. [Journal Article]Sheng Li Xue Bao. 2022 Dec 25; 74(6):993-1004.SL
- A large number of β-adrenergic receptor (β-AR) agonists and antagonists are widely used in the treatment of cardiovascular diseases and other diseases. Nonetheless, it remains unclear whether these commonly used β-AR drugs can activate downstream β- arrestin-biased signaling pathways. The objective of this study was to investigate β-arrestin2 recruitment effects of β-AR agonists and antagonists t…
- Off-target pharmacological profiling of synthetic cannabinoid receptor agonists including AMB-FUBINACA, CUMYL-PINACA, PB-22, and XLR-11. [Journal Article]
- Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances that have been associated with multiple instances and types of toxicity. Some SCRAs appear to carry a greater toxicological burden than others, or compared to the prototypical cannabis-derived agonist Δ9-tetrahydrocannabinol (Δ9-THC), despite a common primary mechanism of action via cannabinoid 1 (C…
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- MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome. [Journal Article]
- The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues ca…
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- Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics. [Review]Neuropharmacology. 2022 Dec 28; 226:109408.N
- Opioid receptors are G protein-coupled receptors (GPCRs) that regulate activity within peripheral, subcortical and cortical circuits involved in pain, reward, and aversion processing. Opioid receptors are expressed in both presynaptic terminals where they inhibit neurotransmitter release and postsynaptic locations where they act to hyperpolarize neurons and reduce activity. Agonist activation of …
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- Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis. [Journal Article]Clin Immunol. 2022 Dec 26; 247:109219.CI
- CONCLUSIONS: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.
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- Novel small molecule MRGPRX2 antagonists inhibit a murine model of allergic reaction. [Journal Article]J Allergy Clin Immunol. 2022 Dec 26 [Online ahead of print]JA
- CONCLUSIONS: The small molecules might hold a significant therapeutic promise to treat MRGPRX2-mediated allergies and inflammation.
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- IFT20 confers paclitaxel resistance by triggering β-arrestin-1 to modulate ASK1 signaling in breast cancer. [Journal Article]Mol Cancer Res. 2022 Dec 27 [Online ahead of print]MC
- System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer. Here, we demonstrate that IFT20 is positively associated with shorter…
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- Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2. [Journal Article]J Cell Biochem. 2022 Dec 24 [Online ahead of print]JC
- The complement system is central to the rapid immune response witnessed in vertebrates and invertebrates, which plays a crucial role in physiology and pathophysiology. Complement activation fuels the proteolytic cascade, which produces several complement fragments that interacts with a distinct set of complement receptors. Among all the complement fragments, C5a is one of the most potent anaphyla…
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- Minocycline Inhibits Microglial Activation and Improves Visual Function in a Chronic Model of Age-Related Retinal Degeneration. [Journal Article]
- Age-related macular degeneration (AMD) is a chronic disease, which progresses slowly from early to late stages over many years. Inflammation critically contributes to the pathogenesis of AMD. Here, we investigated the therapeutic potential of minocycline in a chronic model of AMD (i.e., the LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout [DKO] mice). Five-month-old DKO and wild type (WT) (Socs3fl…
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- Endothelial β-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia. [Journal Article]
- Modulation of endothelial cell behavior and phenotype by hemodynamic forces involves many signaling components, including cell surface receptors, intracellular signaling intermediaries, transcription factors, and epigenetic elements. Many of the signaling mechanisms that underlie mechanotransduction by endothelial cells are inadequately defined. Here we sought to better understand how β-arrestins…
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- Predicting the response to GLP-1 receptor agonists: an unexpected role for β-arrestin-1. [Journal Article]Lancet Diabetes Endocrinol. 2023 Jan; 11(1):3-4.LD
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- Structural basis for Y2 receptor-mediated neuropeptide Y and peptide YY signaling. [Journal Article]Structure. 2023 Jan 05; 31(1):44-57.e6.S
- Neuropeptide Y (NPY) and its receptors are expressed in various human tissues including the brain where they regulate appetite and emotion. Upon NPY stimulation, the neuropeptide Y1 and Y2 receptors (Y1R and Y2R, respectively) activate GI signaling, but their physiological responses to food intake are different. In addition, deletion of the two N-terminal amino acids of peptide YY (PYY(3-36)), th…
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