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Institut National de la Santé et de la Recherche Médicale Unité 36, Collège de France, 75005 Paris, France
The structural
determinants of the rat angiotensin (ANG) II
AT1A receptor involved in receptor
internalization, desensitization, and activation are investigated by
producing six mutants that had progessively larger deletions of the
cytoplasmic tail (
13, 19, 24, 31,
46, and 56 residues, respectively). After stable transfection of the cDNAs into Chinese hamster ovary cells, all mutants, except the most truncated, exhibit normal
[Sar1]ANG II
affinities [dissociation constant
(Kd) = 0.19-0.70 nM] compared with the wild-type (WT) receptor
(Kd = 0.62 nM)
and are able to activate a Gq/11
protein and a phospholipase C as measured by the ANG II-induced
inositol phosphate (IP) turnover in the different clones. However, one
of these mutants, 
329 (deletion of 31 residues), exhibits a peculiar
phenotype. This mutant shows a reduced ligand-induced internalization
as measured by the acid-washing procedure (only 32% of receptors are
internalized vs. 83% for WT). Moreover, the 329 mutant is less
desensitized by a pretreatment with either ANG II (15% desensitization
of ANG II-stimulated IP turnover vs. 60% for WT receptor) or the
phorbol ester phorbol 12-myristate 13-acetate (no desensitization vs.
29% for WT receptor). These functional modifications of the 329
mutant are associated with the transduction of an amplified signal as
demonstrated on both IP turnover and an integrated physiological effect
of ANG II. Taken together, these data indicate that the sequence
329SLSTKMS335
of the rat AT1A receptor is
involved in both receptor internalization and desensitization. This is
the first demonstration that a desensitization- and
internalization-defective AT1A
receptor mutant is also hyperreactive and mediates augmented cellular
responses.
angiotensin II receptor; mutagenesis; endocytosis; Chinese hamster ovary cells
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