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    G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor (2005)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Kostenis, Evi
    Milligan, Graeme
    Christopoulos, Arthur
    Sanchez-Ferrer, Carlos F
    Heringer-Walther, Silvia
    Sexton, Patrick M
    Gembardt, Florian
    Kellett, Elaine
    Martini, Lene
    Vanderheyden, Patrick
    Schultheiss, Heinz-Peter
    Walther, Thomas
    Quelle
    Circulation; 111(14) — S. 1806–1813
    ISSN: 0009-7322
    Sprache
    Englisch
    Verweise
    Pubmed: 15809376
    Kontakt
    Institut für Tierpathologie

    Robert-von-Ostertag-Str. 15
    Gebäude 12
    14163 Berlin
    Tel.+49 30 838 62450 Fax.+49 30 838 62522

    Abstract / Zusammenfassung

    We previously identified the G-protein-coupled receptor Mas, encoded by the Mas proto-oncogene, as an endogenous receptor for the heptapeptide angiotensin-(1-7); however, the receptor is also suggested to be involved in actions of angiotensin II. We therefore tested whether this could be mediated indirectly through an interaction with the angiotensin II type 1 receptor, AT1.

    In transfected mammalian cells, Mas was not activated by angiotensin II; however, AT1 receptor-mediated, angiotensin II-induced production of inositol phosphates and mobilization of intracellular Ca2+ was diminished by 50% after coexpression of Mas, despite a concomitant increase in angiotensin II binding capacity. Mas and the AT1 receptor formed a constitutive hetero-oligomeric complex that was unaffected by the presence of agonists or antagonists of the 2 receptors. In vivo, Mas acts as an antagonist of the AT1 receptor; mice lacking the Mas gene show enhanced angiotensin II-mediated vasoconstriction in mesenteric microvessels.

    These results demonstrate that Mas can hetero-oligomerize with the AT1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor. Consequently, the AT1-Mas complex could be of great importance as a target for pharmacological intervention in cardiovascular diseases.