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The endogenous ligand Stunted of the GPCR Methuselah extends lifespan in Drosophila

Nature Cell Biology volume 6, pages 540–546 (2004)Cite this article

Abstract

Many extracellular signals are transmitted to the interior of the cell by receptors with seven membrane-spanning helices that trigger their effects by means of heterotrimeric guanine-nucleotide-binding regulatory proteins (G proteins)1,2,3,4. These G-protein-coupled receptors (GPCRs) control various physiological functions in evolution from pheromone-induced mating in yeast to cognition in humans5,6. The potential role of the G-protein signalling system in the control of animal ageing has been highlighted by the genetic revelation that mutation of a GPCR encoded by methuselah extends the lifespan of adult Drosophila flies7. How methuselah functions in controlling ageing is not clear. A first essential step towards the understanding of methuselah function is to determine the ligands of Methuselah. Here we report the identification and characterization of two endogenous peptide ligands of Methuselah, designated Stunted A and B. Flies with mutations in the gene encoding these ligands show an increase in lifespan and resistance to oxidative stress. We conclude that the Stunted–Methuselah system is involved in the control of animal ageing.

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Figure 1: Purification of endogenous ligands of the Mth receptor.
Figure 2: Synthetic peptide ligands of Mth.
Figure 3: Lifespan extension of sun mutant adult flies.
Figure 4: sun mutant flies show increased resistance to oxidative stress.

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Acknowledgements

We thank M. Young in whose laboratory the fly genetic work was done; T. Lieber and S. Kidd for advice and help; A. Katzen for the sunEM67 strain and its parental and rescuing fly strains; T. Kidd and D. Ish-Horowicz for the sunY6 strain and its parental fly strains; M. Lu and T. Maack for the use of their HPLC instruments; and D. McGarrigle for reading the manuscript. Mass spectrometric analyses and peptide sequencing were provided by the Rockefeller University Protein/DNA Technology Center. This work was supported by grants from the NIH (to X.-Y.H., M.Y. and Y.B.). X.-Y.H. is an Established Investigator of the American Heart Association, a Career Scientist of the Irma T. Hirschl Trust, and a Charles H. Leach Foundation Research Scholar.

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  1. Department of Physiology, Cornell University Weill Medical College, New York, 10021, New York, USA

    Svetlana Cvejic, Zheng Zhu, Sarah J. Felice & Xin-Yun Huang

  2. Department of Pharmacology, New York University School of Medicine, New York, 10016, New York, USA

    Yemiliya Berman

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  1. Svetlana Cvejic
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Correspondence to Xin-Yun Huang.

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Cvejic, S., Zhu, Z., Felice, S. et al. The endogenous ligand Stunted of the GPCR Methuselah extends lifespan in Drosophila. Nat Cell Biol 6, 540–546 (2004). https://doi.org/10.1038/ncb1133

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