Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 S3.2

ECE2007 Symposia Signaling and regulation of G-protein-coupled hormone receptors (4 abstracts)

Pharmacological chaperones rescue the membrane expression and function of a mutant of the vasopressin V1b/V3 receptor

Eric Clauser , Jessica Robert , Colette Auzan & Marie Ange Ventura


Institut Cochin, INSERM U567, Paris, France, CNRS UMR8104, Paris, France; University Paris V, Paris, France.

The majority of loss-of function mutations of G protein coupled receptors, leading to diseases, such as diabetes insipidus (V2 vasopressin receptor) or retinitis pigmentosa (rhodopsin) are consecutive to retention of the receptor in the endoplasmic reticulum (ER). Cell surface expression and biological function can be restored by membrane-permeable ligands called pharmacological chaperones. The V1b/V3R, one of the 3 subtypes of vasopressin receptors, is involved in the regulation of the corticotroph axis during stress. Using an original assay for cell surface expression of the receptor, we have demonstrated that a mutation of the hydropobic 341FNX2LLX3L350 motif in the C-terminus of the human pituitary V1b/V3R (MUT V3R) leads to its retention in the ER. The precise role of this motif was further investigated using SSR149415, a nonpeptide V1b/V3R antagonist.

The absence of the mutated receptor at the plasma membrane is linked to its prolonged association with the molecular chaperone, calnexine, in the ER and to its intensive degradation by the ubiquitin-proteasomal machinery. However, this ER retention is not a consequence of a lack of oligomerization of the mutant, which can be identified as dimers in the ER with BRET technique.

Treatment with SSR149415 restores expression of the mutated receptor at the cell surface and its correct maturation, resulting into the functional recovery of its signaling properties. SSR149415 acts by stabilizing the native-like conformation of the V1b/V3R, reducing its association with calnexin and favoring a secretory pathway rather than the proteasomal degradation pathway.

In conclusion, the 341FNX2LLX3L350 sequence is an important motif for the V1b/V3R conformation and the misfolfding resulting from its mutation alters the receptor export but can be reverted by SSR149415, which behaves as a pharmacological chaperone.

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