Cryo-EM structure of the formoterol-bound turkey beta1 adrenoceptor coupled to beta-arrestin-1 with bound Fab30 in lipid nanodisc
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Lee
PROVIDER: EMPIAR-10342 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
Molecular basis of β-arrestin coupling to formoterol-bound β<sub>1</sub>-adrenoceptor.
Lee Yang Y Warne Tony T Nehmé Rony R Pandey Shubhi S Dwivedi-Agnihotri Hemlata H Chaturvedi Madhu M Edwards Patricia C PC García-Nafría Javier J Leslie Andrew G W AGW Shukla Arun K AK Tate Christopher G CG
Nature 20200617 7818
The β<sub>1</sub>-adrenoceptor (β<sub>1</sub>AR) is a G-protein-coupled receptor (GPCR) that couples<sup>1</sup> to the heterotrimeric G protein G<sub>s</sub>. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces G<sub>s</sub> and induces signalling through the MAP kinase pathway<sup>2</sup>. The ability of synthetic agonists to induce signalling p ...[more]
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Project description:Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β(3)-AR agonist), and formoterol (selective β(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of β(2)-AR ligands for therapeutic MB.
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