Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor

L. Hunyady, Z. Gáborik, Bukhtiar H. Shah, Gowraganahalli Jagadeesh, Adrian J L Clark, Kevin J. Catt

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Angiotensin II (Ang II) regulates aldosterone secretion by stimulating inositol phosphate production and Ca2+ signaling in adrenal glomerulosa cells via the Gq-coupled AT1 receptor, which is rapidly internalized upon agonist binding. Ang II also binds to the heptahelical AT2 receptor, which neither activates inositol phosphate signaling nor undergoes receptor internalization. The differential behaviors of the AT1 and AT2 receptors were analyzed in chimeric angiotensin receptors created by swapping the second (IL2), the third (IL3) intracellular loops and/or the cytoplasmic tail (CT) between these receptors. When transiently expressed in COS-7 cells, the chimeric receptors showed only minor alterations in their ligand binding properties. Measurements of the internalization kinetics and inositol phosphate responses of chimeric AT 1A receptors indicated that the CT is required for normal receptor internalization, and IL2 is a determinant of G protein activation. In addition, the amino-terminal portion of IL3 is required for both receptor functions. However, only substitution of IL2 impaired Ang II-induced ERK activation, suggesting that alternative mechanisms are responsible for ERK activation in signaling-deficient mutant AT1 receptors. Substitution of IL2, IL3, or CT of the AT1A receptor into the AT2 receptor sequence did not endow the latter with the ability to internalize or to mediate inositol phosphate signaling responses. These data suggest that the lack of receptor internalization and inositol phosphate signal generation by the AT2 receptor is a consequence of its different activation mechanism, rather than the inability of its cytoplasmic domains to couple to intracellular effectors.

Original languageEnglish
Pages (from-to)89-100
Number of pages12
JournalMolecular and Cellular Endocrinology
Volume217
Issue number1-2
DOIs
Publication statusPublished - Mar 31 2004

Fingerprint

Angiotensin Type 1 Receptor
Inositol Phosphates
Chemical activation
Angiotensin II
Interleukin-2
Substitution reactions
Zona Glomerulosa
Angiotensin Receptors
Interleukin-2 Receptors
COS Cells
Cytoplasmic and Nuclear Receptors
Aldosterone
GTP-Binding Proteins
Ligands
Kinetics

Keywords

  • Angiotensin II
  • Ca signaling
  • Inositol phosphate responses
  • Receptor internalization
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor. / Hunyady, L.; Gáborik, Z.; Shah, Bukhtiar H.; Jagadeesh, Gowraganahalli; Clark, Adrian J L; Catt, Kevin J.

In: Molecular and Cellular Endocrinology, Vol. 217, No. 1-2, 31.03.2004, p. 89-100.

Research output: Contribution to journalArticle

Hunyady, L. ; Gáborik, Z. ; Shah, Bukhtiar H. ; Jagadeesh, Gowraganahalli ; Clark, Adrian J L ; Catt, Kevin J. / Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor. In: Molecular and Cellular Endocrinology. 2004 ; Vol. 217, No. 1-2. pp. 89-100.
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