CFTR mutation, various deletions/substitutions in the vasopressin receptor result in a protein-trafficking defect. Failure of the newly synthesized vasopressin receptor protein to move from the ER to the plasma membrane disrupts the normal regulation of water transport in the cell (12). Patients suffering from this malady, referred to as nephrogenic diabetes insipidus, are unable to properly reabsorb water in the kidney and develop a number of metabolic disorders. In a clever twist, Morello and colleagues (11) examined the effects of a receptor antagonist (SR121463A) on the maturation of a trafficking-defective vasopressin receptor mutant protein. Treatment of the cells for about 16 hours with this membrane-permeable antagonist resulted in a portion of the newly synthesized vasopressin receptor to exit the ER and move to the plasma membrane. After removal of the compound, these cells bound vasopressin peptide hormone and activated adenylate cyclase, similar to that observed for cells expressing the wild-type receptor. The increases in the amount of the mutant receptor that reached the plasma membrane were both dose and time-dependent.

Antagonist concentrations of around 100 nM were effective (about 1000 times less than the concentration of cellular osmolytes needed to correct the∆ F508 CFTR folding mutant). Moreover, incubating cells with a membrane-impermeable peptide failed to rescue the folding of the mutant vasopressin receptor. Finally, 7 other trafficking-defective vasopressin mutants also were observed to move to the plasma membrane in response to either added SR121463A, or another cellpermeable receptor antagonist.