Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2

Cell Reports, Journal Year: 2023, Volume and Issue: 42(11), P. 113406 - 113406

Published: Nov. 1, 2023

Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, MK-6892 and GSK256073, with fewer adverse have been created. However, activation mechanism of niacin these new agonists not well understood. Here, we present three cryoelectron microscopy structures Gi-coupled bound to niacin, MK-6892, GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced aromatic amino clusters (W91ECL1, H1614.59, W1885.38, H1895.39, F1935.43) from receptors ECL1, TM4, TM5. Additionally, conserved residues R1113.36 Y2847.43, unique HCA family, likely initiate signal propagation HCAR2. This study provides insights into ligand recognition, activation, G protein coupling mediated laying groundwork for developing HCAR2-targeted drugs.

Language: Английский

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Adenylosuccinic Acid: An Orphan Drug with Untapped Potential

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(6), P. 822 - 822

Published: May 31, 2023

Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates purine recycling and energy homeostasis but might also be crucial averting inflammation other forms of cellular stress during intense demand maintaining tissue biomass glucose disposal. This article documents the known biological functions explores its potential treatment neuromuscular chronic diseases.

Language: Английский

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Fasting-mimicking diet alleviates inflammatory pain by inhibiting neutrophil extracellular traps formation and neuroinflammation in the spinal cord

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 21, 2023

Neutrophil extracellular traps (NETs) promote neuroinflammation and, thus, central nervous system (CNS) disease progression. However, it remains unclear whether CNS-associated NETs affect pain outcomes. A fasting-mimicking diet (FMD) alleviates neurological disorders by attenuating and promoting nerve regeneration. Hence, in this study, we explore the role of CNS during acute investigate FMD inhibiting relieving pain.The inflammatory model was established injecting complete Freund's adjuvant (CFA) into hind paw mice. The regimen performed perioperative period. PAD4 siRNA or CI-amidine (PAD4 inhibitor) used to inhibit formation NETs. Monoamine oxidase-B (MAO-B) knockdown occurred AAV-GFAP-shRNA AAV-hSyn-shRNA inhibited selegiline (an MAO-B inhibitor). changes NETs, neuroinflammation, related signaling pathways were examined western blot, immunofluorescence, ELISA, flow cytometry.In phase pain, accumulate spinal cords This is associated with exacerbated neuroinflammation. Meanwhile, inhibition allodynia CFA inhibits production which enhanced treatment inhibitor CI-amidine, reversed inducer phorbol 12-myristate 13-acetate (PMA). Mechanistically, neutrophil-recruiting pathway MAO-B/5-hydroxyindoleacetic acid (5-HIAA) / G-protein-coupled receptor 35 (GPR35) NETs-inducing MAO-B/ Reactive oxygen species (ROS) are significantly upregulated development pain. largely expressed astrocytes neurons effectively attenuates CFA-induced formation, cord. Moreover, within rescue experiments, inhibitors synergistically enhance FMD-induced relief, inhibition, attenuation, whereas supplementation downstream molecules (i.e., 5-HIAA PMA) abolished effect.Neutrophil-released cord contribute development. NETs-induced MAO-B/5-HIAA/GPR35 MAO-B/ROS neurons, thereby Video Abstract.

Language: Английский

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Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2

Cell Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: Nov. 28, 2023

Abstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty formation humans. It is deeply involved many pathophysiological processes serves as an attractive target for treatment cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, metabolic diseases. Here, we report four cryo-EM structures human HCAR2–Gi1 complexes or without agonists, including drugs niacin (2.69 Å) acipimox (3.23 Å), highly subtype-specific agonist MK-6892 (3.25 apo form (3.28 Å). Combined molecular dynamics simulation functional analysis, have revealed recognition mechanism HCAR2 different agonists summarized general pharmacophore features which are based on three residues R111 3.36 , S179 45.52 Y284 7.43 . Notably, MK-6892–HCAR2 structure shows extended binding pocket relative other agonist-bound complexes. In addition, that determine ligand selectivity between HCAR3 also illuminated. Our findings provide structural insights into recognition, selectivity, activation, protein coupling HCAR2, shed light design new HCAR2-targeting greater efficacy, higher fewer no side effects.

Language: Английский

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Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(4), P. 1164 - 1177

Published: March 1, 2024

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia. Gamma oscillations are a widely recognized hallmark abnormal neural electrical activity in Currently, studies have reported increased oscillation power cases However, little is known about how other electrophysiological parameters gamma altered Furthermore, role dopamine D3 receptor, which implicated dyskinesia, movement disorder-related changes unclear. We found that cortico-striatal functional connectivity beta was enhanced model Parkinson’s disease. application cortical projections and aperiodic components, as well bidirectional primary motor cortex (M1) ↔ dorsolateral striatum flow. Administration PD128907 (a selective receptor agonist) induced dyskinesia excessive with M1 PG01037 antagonist) attenuated suppressed decreased causality → direction. These findings suggest plays dyskinesia-related oscillatory activity, it has potential therapeutic target for

Language: Английский

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The survival of B cells is compromised in kidney disease

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 30, 2024

Antibody-mediated protection against pathogens is crucial to a healthy life. However, the recent SARS-CoV-2 pandemic has shown that pre-existing comorbid conditions including kidney disease account for compromised humoral immunity infections. Individuals with are not only susceptible infections but also exhibit poor vaccine-induced antibody response. Using multiple mouse models of disease, we demonstrate renal dysfunction inhibits germinal center (GC) response T-dependent antigens. GC B cells increased apoptosis in disease. Uremic toxin hippuric acid drives loss mitochondrial membrane potential, leading G-protein-coupled receptor 109A dependent manner. Finally, and titer diminished mice following influenza virus infection, major cause mortality individuals disorders. These results provide mechanistic understanding how suppresses patients

Language: Английский

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Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(10), P. 11646 - 11664

Published: Oct. 19, 2024

Neurodegenerative disorders, particularly Alzheimer's and Parkinson's diseases, continue to challenge modern medicine despite therapeutic advances. Orphan G-protein-coupled receptors (GPCRs) have emerged as promising targets in the central nervous system, offering new avenues for drug development. This review focuses on structural biology of orphan GPCRs implicated these providing a comprehensive analysis their molecular architecture functional mechanisms. We examine recent breakthroughs determination techniques, such cryo-electron microscopy X-ray crystallography, which elucidated intricate conformations receptors. The highlights how insights inform our understanding GPCR activation, ligand binding signaling pathways. By integrating data with pharmacology, we explore potential structure-guided approaches developing targeted therapeutics toward GPCRs. structural-biology-centered perspective aims deepen comprehension guide future discovery efforts neurodegenerative disorders.

Language: Английский

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Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE‐1 Inhibitors Against Alzheimer's Disease by In Silico, In Vitro, and In Vivo Studies

Phytotherapy Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate slow down progression multifactorial diseases, we evaluated potential ability CBDA CBGA also inhibit enzymes involved in modulation cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational biochemical studies was pursued selected enzymes, followed behavioral electrophysiological experiments an AD mouse model. The β-arrestin assay GPR109A qPCR TRPM7 were carried out. effective both acetyl- butyryl-cholinesterases (AChE/BuChE), well β-secretase-1 (BACE-1) low micromolar range, they prevent aggregation fibrils. Computational provided rationale for competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile two ligands. repeated treatment with (10 mg/kg, i.p.) improved cognitive deficit induced peptide. recovery long-term potentiation hippocampus observed, where restored physiological expression level TRPM7, receptor channel neurodegenerative diseases. We showed that these do not stimulate assay. Collectively, data broaden pharmacological suggest their use novel anti-AD MTDLs.

Language: Английский

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Anthranilic Acid–G-Protein Coupled Receptor109A–Cytosolic Phospholipase A2–Myelin–Cognition Cascade: A New Target for the Treatment/Prevention of Cognitive Impairment in Schizophrenia, Dementia, and Aging

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13269 - 13269

Published: Dec. 10, 2024

Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive Alzheimer’s dementia) neurodegenerative diseases. Limited efficacy current pharmacological treatments warrants further search for new targets nootropic interventions. The breakdown myelin, phospholipids axonal sheath that protects the conduction nerve impulse between neurons, was proposed as neuropathological abnormality precedes promotes deposition amyloid-β in neuritic plaques. present review recent literature our own pre- clinical data suggest (for first time) anthranilic acid (AA)-induced activation microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme triggers degradation myelin consequently attenuates impairment. suggests up-regulation AA formation sex-specific compensatory (adaptive) reaction aimed to prevent/treat AA–GPR109A–cPLA2–myelin–cognition cascade interventions, e.g., administration pegylated kynureninase, catalyzes from Kynurenine (Kyn), tryptophane catabolite; interferon-alpha; central peripheral Kyn aminotransferase inhibitors increase availability substrate formation; vagus stimulation. predicts activity exogenous GPR109A agonists were designed underwent trials (unsuccessful) anti-dyslipidemia agents. might contribute pathogenesis Data on disorders are scarce, needs exploration studies

Language: Английский

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Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 29, 2023

Abstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G-protein-coupled receptors with key roles in regulating lipolysis and free fatty formation humans. It is deeply involved many pathophysiological processes serves as an attractive target for treatment neoplastic, autoimmune, neurodegenerative, inflammatory, metabolic diseases. Here, we report four cryo-EM structures human HCAR2-Gi1 complexes or without agonists, including drugs niacin acipimox, highly subtype-specific agonist MK-6892. Combined molecular docking functional analysis, have revealed recognition mechanism HCAR2 different agonists summarized general pharmacophore features which are based on three residues R111 3.36 , S179 45.52 Y284 7.43 . Notably, MK-6892-HCAR2 structure shows extended binding pocket relative other agonist-bound complexes. In addition, that determine ligand selectivity between HCAR3 also illuminated. Our findings provide structural insights into recognition, selectivity, activation, G protein coupling HCAR2, sheds light design new HCAR2-targeting greater efficacy, higher fewer no side effects.

Language: Английский

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