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Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14

Nature volume 401, pages 282–286 (1999)Cite this article

An Erratum to this article was published on 23 December 1999

Abstract

Urotensin-II (U-II) is a vasoactive ‘somatostatin-like’ cyclic peptide which was originally isolated from fish spinal cords1,2, and which has recently been cloned from man3. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 (refs 4, 5) and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities.

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Figure 1: Alignment of rat (r) and human (h) GPR14 polypeptide sequences.
Figure 2: GPR14 is a U-II receptor.
Figure 3: Nucleotide and deduced peptide sequence of human U-II propeptide cDNA.
Figure 4: Human U-II is a potent vasoconstrictor.
Figure 5: Human U-II produces cardiovascular dysfunction in the anaesthetized monkey.

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Acknowledgements

We dedicate this Letter to the memory of our friend and colleague, the late J. M. Stadel. We thank D. Ashton, P. Buckley, T. Covatta, J. Culp, G. Dytko, L. Floyd, P. Hieble, M. Luttmann, G. McCafferty, D. Naselsky, P. Nuthulaganti, P. Ryan and A. Sulpizio for their assistance and comments during the preparation of this manuscript. We thank B. O'Dowd, University of Toronto for the rat GPR14 cDNA clone.

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Author notes

  1. Robert S. Ames and Henry M. Sarau: These authors contributed equally to this work

Authors and Affiliations

  1. Departments of Molecular Biology,

    Robert S. Ames, Catherine E. Ellis, Nabil A. Elshourbagy & Usman Shabon

  2. Departments of Pulmonary and Cardiovascular Pharmacology, ,

    Henry M. Sarau, Robert N. Willette, Nambi V. Aiyar, Anne M. Romanic, James J. Foley, Charles F. Sauermelch, Zhaohui Ao, Jyoti Disa, Jeffrey M. Stadel, Douglas W. P. Hay, Eliot H. Ohlstein & Stephen A. Douglas

  3. Departments of Functional Gene Analysis,

    Johathan K. Chambers & Shelagh Wilson

  4. Departments of Pathology,

    Calvert S. Louden

  5. Laboratory Animal Sciences,

    Robert W. Coatney

  6. Departments of Immunology,

    Stephen D. Holmes

  7. Protein Biochemistry and ,

    John D. Martin, Wu-Schyong Liu, George I. Glover & Dean E. McNulty

  8. Gene Expression Sciences, Smith Kline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, 19406-0939, Pennsylvania, USA

    John J. Trill

  9. Southern Way, Harlow, Essex, CM19 5AW, UK

    John J. Trill

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Correspondence to Robert S. Ames.

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Ames, R., Sarau, H., Chambers, J. et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401, 282–286 (1999). https://doi.org/10.1038/45809

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