Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Succinate is a pivotal tricarboxylic acid cycle metabolite but also specifically activates the G i ‐ and q ‐coupled succinate receptor 1 (SUCNR1). Contradictory roles of succinate‐SUCNR1 signaling include reports about its anti‐ or pro‐inflammatory effects. The link between cellular metabolism localization‐dependent SUCNR1 qualifies as potential cause for reported conflicts. To systematically address this connection, we used diverse set methods, including several bioluminescence resonance energy transfer‐based biosensors, dynamic mass redistribution measurements, second messenger kinase phosphorylation assays, calcium imaging, metabolic analyses. Different states were mimicked using glucose (Glc) glutamine (Gln) available substrates to provoke differential endogenous (SUC) production. We show that signaling, localization, are mutually dependent, with showing distinct spatial substrate‐dependent protein activation. found Gln‐consumption associated higher rate oxidative causes increased extracellular SUC concentrations, accompanied by internalization, reduced miniG recruitment plasma membrane, lower Ca 2+ signals. In Glc, under basal conditions, stronger than activation, while opposite true upon stimulation an agonist. addition, interacts proteins in endosomal compartments. THP‐1 cells, polarized M2‐like macrophages, SUCNR1‐mediated stimulates glycolysis, inhibits glycolytic rate. Our results suggest context determines spatially dependent which turn modulates homeostasis mediates adaptations changes concentrations.

Language: Английский

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Management succinate release through SDHA by G protein-coupled receptor 91 signal, TRAP1, and SIRT3 regulation in lung cancer cells by NAR nanoparticles

Journal of Genetic Engineering and Biotechnology, Journal Year: 2025, Volume and Issue: 23(1), P. 100464 - 100464

Published: Feb. 11, 2025

Language: Английский

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Structural insights into ligand recognition and activation of the succinate receptor SUCNR1

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114381 - 114381

Published: June 25, 2024

Succinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as stress signal through receptor (SUCNR1), class A G protein-coupled receptor. Research on signaling is hampered by the lack of high-resolution structures agonist-bound We present cryoelectron microscopy (cryo-EM) SUCNR1-Gi complexes bound to its non-metabolite derivative cis-epoxysuccinate. Key determinants for recognition cis conformation include R2817.39 Y832.64, while Y301.39 R993.29 participate binding both loop 2, F175ECL2 β-hairpin, forms hydrogen bond with caps pocket. At receptor-Gi interface, agonist induces rearrangement hydrophobic network transmembrane (TM)5 TM6, leading TM TM3 TM7. These findings extend our understanding SUCNR1, aiding development therapeutics

Language: Английский

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A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells

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

Published: Nov. 28, 2024

Abstract Cellular responses to stimuli underpin discoveries in drug development, synthetic biology, and general life sciences. We introduce a library comprising 6144 promoters, each shorter than 250 bp, designed as transcriptional readouts of cellular stimulus massively parallel reporter assay format. This facilitates precise detection amplification activity from our enabling the systematic development tunable reporters with dynamic ranges 50−100 fold. Our proved functional numerous cell lines responsive variety stimuli, including metabolites, mitogens, toxins, pharmaceutical agents, generating robust scalable effective screening assays, biomarkers, circuits attuned endogenous activities. Particularly valuable therapeutic excels capturing candidate signals mediated by targets, feature we illustrate across nine diverse G-protein coupled receptors (GPCRs), critical targets development. detail how this tool isolates defines discrete signaling pathways associated specific GPCRs, elucidating their signatures. With its ease implementation, broad utility, publicly available data, comprehensive documentation, will be beneficial engineering, ligand exploration,

Language: Английский

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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

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

Published: June 25, 2024

Abstract A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with protein binding—and back – is revealed by a puzzle thirty novel 3D structures hydroxycarboxylic acid 2 (HCAR2) in complex eight different orthosteric and single agonist. HCAR2 sensor β-hydroxybutyrate, niacin certain anti-inflammatory drugs. Surprisingly, without on-target side effects bound very similarly completely occluded binding site. Thus, despite many we are still left pertinent need to understand molecular dynamics this similar systems.

Language: Английский

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Molecular activation and G protein coupling selectivity of human succinate receptor SUCR1

Cell Research, Journal Year: 2024, Volume and Issue: 34(8), P. 590 - 593

Published: May 14, 2024

Language: Английский

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Molecular basis of ligand recognition and activation of the human succinate receptor SUCR1

Cell Research, Journal Year: 2024, Volume and Issue: 34(8), P. 594 - 596

Published: June 4, 2024

Language: Английский

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Exploring Holy Basil’s Bioactive Compounds for T2DM Treatment: Docking and Molecular Dynamics Simulations with Human Omentin-1

Cell Biochemistry and Biophysics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Language: Английский

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