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A noninternalized nondesensitized truncated AT1A receptor transduces an amplified ANG II signal

S Conchon1, N Peltier, P Corvol

  • 1Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, Paris, France.

The American Journal of Physiology
|March 5, 1998
PubMed

Insights

Researchers studied rat angiotensin II AT1A receptor mutants to understand internalization and desensitization. A specific mutant (delta 329) showed impaired internalization and desensitization, leading to amplified cellular responses.

Area of Science:

  • Molecular Pharmacology
  • Cell Signaling
  • Receptor Biology

Background:

  • The angiotensin II AT1A receptor plays a crucial role in cardiovascular regulation.
  • Receptor internalization and desensitization are key mechanisms modulating cellular responses to angiotensin II.
  • Understanding the structural basis of these processes is vital for developing targeted therapies.

Purpose of the Study:

  • To identify structural determinants within the cytoplasmic tail of the rat AT1A receptor responsible for internalization and desensitization.
  • To investigate the functional consequences of impaired internalization and desensitization on receptor signaling.
  • To characterize a novel AT1A receptor mutant with altered desensitization and internalization properties.

Main Methods:

  • Generation of six rat AT1A receptor mutants with progressive deletions in the cytoplasmic tail.
  • Stable transfection into Chinese hamster ovary cells and assessment of [Sar1]ANG II binding affinities (Kd).
  • Measurement of ANG II-induced inositol phosphate (IP) turnover, receptor internalization (acid-washing), and desensitization (ANG II or phorbol ester pretreatment).

Main Results:

  • Most mutants retained normal ligand binding affinities and Gq/11 protein/phospholipase C activation.
  • The delta 329 mutant (31 residue deletion) exhibited significantly reduced ligand-induced internalization (32% vs. 83% WT).
  • Delta 329 displayed diminished desensitization to ANG II (15% vs. 60% WT) and phorbol ester (0% vs. 29% WT), coupled with amplified signaling.

Conclusions:

  • The sequence 329SLSTKMS335 in the rat AT1A receptor cytoplasmic tail is critical for receptor internalization and desensitization.
  • A mutant defective in desensitization and internalization (delta 329) demonstrates hyperreactivity and augmented cellular responses.
  • This study provides the first evidence linking impaired AT1A receptor desensitization/internalization to enhanced signaling and cellular effects.

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