G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression DOI Creative Commons
Naoto Kajitani, Mami Okada‐Tsuchioka, Asuka Inoue

et al.

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 49(3), P. 561 - 572

Published: Sept. 6, 2023

Abstract Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and been considered to be more effective than newer selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds lysophosphatidic acid receptor 1 (LPAR1), G protein-coupled receptor, activates downstream protein signaling, while exerting little effect on β-arrestin recruitment. This suggests amitriptyline acts protein-biased agonist LPAR1. biased agonism was specific not observed with other antidepressants. LPAR1 found involved behavioral amitriptyline. Notably, long-term infusion mouse hippocampus potent LPAR OMPT, but non-biased LPA, induced antidepressant-like behavior, indicating might necessary for effects. Furthermore, RNA-seq analysis revealed LPA OMPT opposite patterns gene expression changes hippocampus. Pathway indicated treatment activated signaling (Rho MAPK), whereas suppressed signaling. Our findings provide insights into mechanisms underlying antidepressant identify promising target development novel

Language: Английский

Molecular recognition of morphine and fentanyl by the human μ-opioid receptor DOI Creative Commons
Youwen Zhuang, Yue Wang, Bingqing He

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4361 - 4375.e19

Published: Nov. 1, 2022

Language: Английский

Citations

161
Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential DOI Creative Commons
Jason Wallach,

Andrew B. Cao,

Maggie M. Calkins

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 15, 2023

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts potential, assessed using head-twitch response (HTR) magnitude in male mice. further disrupting Gq-PLC signaling attenuates the HTR threshold level is required to induce psychedelic-like consistent fact certain partial agonists (e.g., lisuride) are non-psychedelic. Understanding role Gq-efficacy psychopharmacology permits rational development non-psychedelic agonists. also demonstrate block effects downregulation tachyphylaxis. Overall, Gq-signaling can be fine-tuned generate distinct from classical psychedelics.

Language: Английский

Citations

50
Structure-based design of non-hypertrophic apelin receptor modulator DOI Creative Commons
Weiwei Wang,

Su‐Yu Ji,

W. Zhang

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(6), P. 1460 - 1475.e20

Published: Feb. 29, 2024

Language: Английский

Citations

19
Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics DOI Creative Commons
John Janetzko, Ryoji Kise, Benjamin Barsi‐Rhyne

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(24), P. 4560 - 4573.e19

Published: Nov. 1, 2022

Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based in vitro biophysical assays reveal the role membrane phosphoinositides (PIPs) β-arrestin recruitment GPCR-β-arrestin complex dynamics. We find that broadly stratify into two groups, one requires PIP binding does not. Plasma PIPs potentiate an active conformation stabilize complexes by promoting a fully engaged state complex. As allosteric modulators dynamics, allow additional conformational diversity beyond imposed phosphorylation alone. For require recruitment, provides mechanism release upon translocation endosomes, allowing its rapid

Language: Английский

Citations

71
Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling DOI Creative Commons
Mohammad Seyedabadi, Mehdi Gharghabi, Eugenia V. Gurevich

et al.

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 47(7), P. 570 - 581

Published: April 5, 2022

Language: Английский

Citations

47
Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism DOI Creative Commons
Yuying Liao, Huibing Zhang, Qingya Shen

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5784 - 5797.e17

Published: Dec. 1, 2023

Language: Английский

Citations

41
Applications and prospects of cryo-EM in drug discovery DOI Creative Commons

Kongfu Zhu,

Chuang Yuan,

Yongming Du

et al.

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: March 6, 2023

Abstract Drug discovery is a crucial part of human healthcare and has dramatically benefited lifespan life quality in recent centuries, however, it usually time- effort-consuming. Structural biology been demonstrated as powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) emerging the mainstream structure determination biomacromolecules past decade received increasing attention from pharmaceutical industry. Although cryo-EM still limitations resolution, speed throughput, growing number innovative drugs are being developed with help cryo-EM. Here, we aim provide an overview how techniques applied facilitate discovery. The development typical workflow technique will be briefly introduced, followed by its specific applications structure-based design, fragment-based discovery, proteolysis targeting chimeras, antibody repurposing. Besides cryo-EM, innovation involves other state-of-the-art such artificial intelligence (AI), which increasingly active diverse areas. combination AI provides opportunity minimize automation, throughput interpretation medium-resolution maps, tends new direction future rapid make indispensable modern

Language: Английский

Citations

35
Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 DOI Creative Commons
Heng Liu, Qing Zhang, Xinheng He

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 6, 2023

Abstract GPR84 is an orphan class A G protein-coupled receptor (GPCR) that predominantly expressed in immune cells and plays important roles inflammation, fibrosis, metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gα i human bound to a synthetic lipid-mimetic ligand, LY237, or putative endogenous medium-chain fatty acid (MCFA) 3-hydroxy lauric (3-OH-C12). Analysis these two ligand-bound reveals unique hydrophobic nonane tail -contacting patch, which forms blocking wall select MCFA-like agonists with the correct length. We also identify structural features coordinate polar ends LY237 3-OH-C12, including interactions positively charged side chain R172 downward movement extracellular loop 2 (ECL2). Together molecular dynamics simulations functional data, our reveal ECL2 not only contributes direct ligand binding, but pivotal role entry from milieu. These insights into structure function could improve understanding recognition, activation, -coupling GPR84. Our facilitate rational drug discovery against inflammation metabolic disorders targeting

Language: Английский

Citations

31
Cryo-EM structure of the endothelin-1-ETB-Gi complex DOI Creative Commons
Fumiya K. Sano, Hiroaki Akasaka, Wataru Shihoya

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: April 25, 2023

The endothelin ETB receptor is a promiscuous G-protein coupled that activated by vasoactive peptide endothelins. signaling induces reactive astrocytes in the brain and vasorelaxation vascular smooth muscle. Consequently, agonists are expected to be drugs for neuroprotection improved anti-tumor drug delivery. Here, we report cryo-electron microscopy structure of endothelin-1-ETB-Gi complex at 2.8 Å resolution, with assembly stabilized newly established method. Comparisons inactive structures revealed how endothelin-1 activates receptor. NPxxY motif, essential activation, not conserved ETB, resulting unique structural change upon activation. Compared other GPCR-G-protein complexes, binds Gi shallowest position, further expanding diversity binding modes. This information will facilitate elucidation activation rational design agonists.

Language: Английский

Citations

26
Sphingosine-1-Phosphate Signaling in Cardiovascular Diseases DOI Creative Commons
Na Wang, Jingyi Li, Bo Zeng

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(5), P. 818 - 818

Published: May 11, 2023

Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions physiological and pathological conditions by binding activating the three G protein-coupled receptors (S1PR1, S1PR2, S1PR3) expressed endothelial smooth muscle cells, as well cardiomyocytes fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, apoptosis. S1P essential for development of system, abnormal content circulation pathogenesis disorders. This article reviews effects on function mechanisms different types heart blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators S1P-based therapies diseases.

Language: Английский

Citations

26