Angiotensin IV is a potent agonist for constitutive active human AT1 receptors: Distinct roles of the N- and C-terminal residues of angiotensin II during AT1 receptor activation

Minh Tam Le, Patrick M.L. Vanderheyden, Márta Szaszák, Lák, László Hunyady, Georges Vauquelin

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The octapeptide hormone, angiotensin II (Ang II), exerts its major physiological effects by activating AT1 receptors. In vivo Ang II is degraded to bioactive peptides, including Ang III (angiotensin-(2-8)) and Ang IV (angiotensin-(3-8)). These peptides stimulate inositol phosphate generation in human AT1 receptor expressing CHO-K1 cells, but the potency of Ang IV is very low. Substitution of Asn111 with glycine, which is known to cause constitutive receptor activation by disrupting its interaction with the seventh transmembrane helix (TM VII), selectively increased the potency of Ang IV (900-fold) and angiotensin-(4-8), and leads to partial agonism of angiotensin-(5-8). Consistent with the need for the interaction between Arg2 of Ang II and Ang III with Asp281, substitution of this residue with alanine (D281A) decreased the peptide's potency without affecting that of Ang IV. All effects of the D281A mutation were superseded by the N111G mutation. The increased affinity of Ang IV to the N111G mutant was also demonstrated by binding studies. A model is proposed in which the Arg2-Asp281 interaction causes a conformational change in TM VII of the receptor, which, similar to the N111G mutation, eliminates the constraining intramolecular interaction between Asn111 and TM VII. The receptor adopts a more relaxed conformation, allowing the binding of the C-terminal five residues of Ang II that switches this "preactivated" receptor into the fully active conformation.

Original languageEnglish
Pages (from-to)23107-23110
Number of pages4
JournalJournal of Biological Chemistry
Issue number26
Publication statusPublished - Jun 28 2002


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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