Although the activities of the protein synthesis quality control systems are generally advantageous to the cell, on occasion this stringent monitoring process can lead to intracellular retention of salvageable proteins. In recent years, its has been observed that a group of diseases stem from mutations that promote such retention and are collectively referred to as conformational or protein-misfolding diseases (1,2). Nephrogenic diabetes insipidus (NDI) (3,4), which is characterized by a loss of arginine vasopressin (AVP)-mediated antidiuresis, is one of these diseases. In congenital NDI that results from mutations in the AVPR2 gene that encodes the V2 receptor, most missense mutations are misfolded, trapped in the endoplasmic reticulum, and unable to reach the basolateral cell surface to engage the circulating antidiuretic hormone, AVP (5–14).
The natural history of untreated X-linked NDI includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy (15,16). In five new patients who were younger than 1 year and were from North America and in whom we provided molecular testing over the past 12 mo, plasma sodium was in every case >155 mEq/L at the time of diagnosis. We and others initially thought that close monitoring of infants whose AVPR2 mutations were diagnosed pre- or perinatally not only would prevent episodes of dehydration but also would permit close to normal growth and development. Although a low-sodium diet and distal tubule diuretics prescribed to these patients may achieve a 20 to 30% decrease in urine output (17), the low-sodium diet is difficult to follow, and affected children continue to drink large amounts of water. As a result of a physiologic gastroesophageal reflux and to the large amount of water in their stomach, these children often vomit, and, as a consequence, their nutritional intake is not optimal. There is a need, therefore, for a safe further reduction in urine output. We recently used pharmacologic compounds to rescue misfolded mutant V2 receptors by demonstrating in cultured cells that the nonpeptide V2-specific antagonists SR121463A and VPA-985 increased cell surface expression and rescued the signaling activity of seven naturally occurring AVPR2 mutations (185_193del, L59P, L83Q, Y128S, S167L, A294P, and P322H) that are responsible for NDI by promoting their proper folding and maturation (18). These results that suggested that such chaperoning of the receptor could represent a pharmacologic treatment for conformational diseases such as NDI have been confirmed by other investigators (19,20).
Here, we report a short-term trial that was conducted to test the effect of a nonpeptide V1a receptor antagonist on decreasing urine output and increasing urine osmolality in patients with X-linked NDI. We used SR49059, a V1a receptor antagonist that was tested previously in normal volunteers and patients with putative vasopressin excess–related disorders (21–24). In addition, in vitro studies were done to rescue plasma membrane and signaling of a number of mutant V2 receptors with SR49059 and YM087 (Conivaptan), a mixed V1-V2 antagonist (25–29).
Materials and Methods
We tested five adult male patients (weight 83.5 ± 3.9 kg) who had X-linked NDI and bore the following AVPR2 mutations that were identified previously by sequencing: Three patients, who were 20, 42, and 41 yr of age and had R137H (30) (patients 1, 2, and 3); one 21-yr-old with W164S (31) (patient 4); and one 20-yr-old with 185_193del (31) (patient 5). All had a documented lifelong history of polyuria and polydipsia, and extensive previous testing demonstrated a lack of urinary osmolality response to AVP or dDAVP. Specifically, maximal urine osmolalities (mOsm/kg) that were obtained during dDAVP infusions were, respectively, 104, 145, and 248 (patients 1, 2, and 3); 85 (patient 4); and 65 (patient 5) (32). Two patients were being treated with hydrochlorothiazide, which was discontinued for 1 wk before the study. None of the patients described here were considered to have a mild phenotype (9). The following short-term trial conformed to the Declaration of Helsinki and was approved by the Ethics Committee at Ho[Combining Circumflex Accent]pital du Sacre[Combining Acute Accent]-Cœur de Montre[Combining Acute Accent]al, and all participants approved and signed a detailed informed consent.
SR49059 Administration for 2 D.
Patients were tested at the Clinical Research Unit of the Ho[Combining Circumflex Accent]pital du Sacre[Combining Acute Accent]-Coeur de Montre[Combining Acute Accent]al and received a constant Na+, K+, osmotic and caloric diet for the 3 d of the study. A dietitian met the patients before the study and made a detailed evaluation of their usual diet during the previous month. This diet was reproduced for the 3 d of the study. None of these patients followed a sodium-restricted diet. The dietitian met the patients every day during testing and enforced the same diet throughout the study. Water intake was not restricted and was recorded during the 3 d of the study. After 24-h control measurements (day 1, no medication), SR49059 was administered orally for the next 2 d; on day 2, the patients received 150 mg at 8 a.m. and 300 mg at 1:00 p.m. and 6:00 p.m.; on day 3, the patients received 300 mg at 8:00 a.m., 1:00 p.m., and 6:00 p.m. BP and pulse were measured every 30 min from 8:00 a.m. to 12:00 a.m. for the first two patients and every 2 h for the last three patients. Urine volume was obtained by spontaneous voiding every 30 min from 8:00 a.m. to 10:30 p.m. From 10:30 p.m. to 8:00 a.m., depending on individual patients, all urine excretion was measured at unspecific times; urine flow was calculated; and urine osmolality, Na+, K+, and creatinine were measured on these samples. Plasma Na+ and plasma AVP were measured at 7:30 a.m. and 1:30 p.m. each day. Urinary Na+, K+, creatinine, osmolality, and AVP were obtained on each urine sample.
SR49059 Administration for 7 Days.
Two patients who bore the R137H mutation (patients 1 and 3) were also treated 6 wk after the 2-d administration of SR49059 for 7 d with the following dosages of SR49059: 750 mg on day 1 (150 mg at 8:00 a.m., 300 mg at 1:00 p.m., and 300 mg at 6:00 p.m.) and 900 mg (300 mg three times daily) for the following 7 d. Urine and plasma measurements were obtained on days 1, 6, and 9 (postdosing). On days 6 (on SR49059) and 9 (off SR49059), basal plasma samples were obtained for sodium at 8:00 a.m., and urine was obtained every 30 min from 8:30 a.m. to 12:00 p.m. for volume, osmolality, Na+, K+, creatinine, and AVP.
Cell Culture Studies
V2 Receptor Mutant Expression.
Mammalian expression plasmids encoding the wild-type, 12 missense mutations (L59P, L83Q, Y128S, R113W, R137H, W164S, A165D, S167L, I209F, A294P, S315R, and P322H) two in-frame deletions (185_193del and V279del) or five nonsense mutations (W71X, S167X, Q180X, W284X, and R337X) were transiently or stably transfected in COS-1 or HEK 293 cells, as described previously (18,33).
Immunofluorescence Microscopy and Flow Cytometry.
All immunofluorescence and flow cytometry studies were carried out in COS-1 cells or HEK 293 as described previously (18,33). Briefly, V2 receptors were detected using antibodies directed against the myc- or Ha-epitope that was fused at the N-terminus of the constructs. For microscopy, immunoreactivity was assessed using secondary Oregon-green–conjugated anti-mouse antibodies. For flow cytometry, the phycoerythrin-conjugated anti-mouse antibody was used.
Total cAMP accumulation was measured in COS-1 cells or HEK 293 by assessing the transformation of [3H]ATP into [3H]cAMP as described previously (34).
Plasma AVP Measurements.
Plasma AVP was measured by RIA as described previously (35).
Simple statistics were performed for the major variables of interest. Overall results were analyzed by two-way ANOVA. Comparison between time points was performed using paired t test. A two-tailed P < 0.05 was considered statistically significant. Values are reported as mean ± SEM. All analyses were performed with the statistical package SAS (SAS Institute Inc., Cary, NC).
Safety and Efficacy of SR49059 Administration in Adult Patients Who Bear the R137H, W164S, or 185_193del Mutations.
No significant changes in BP and pulse were encountered throughout the study, and no untoward clinical or biochemical abnormalities were observed. Intake and output; plasma sodium and potassium and 24-h urine osmolar excretion; and Na+, K+, and creatinine excretion are presented in Table 1 and Figure 1. SR49059 significantly decreased 24-h urine volume and 24-h water intake from day 1 to day 3. A maximal increase in urine osmolality was observed from 2:00 p.m. to 8:00 p.m. on day 3 (98 ± 22 to 170 ± 52 mOsm/kg; P = 0.05; Figure 1). Plasma Na+ was constant, indicating that the changes in urine volume and water intake were secondary to the SR49059 administration and not to voluntary decrease in water intake that would have led to increased plasma Na+. Individual urine volume and urine osmolality responses are presented for three patients, each bearing a different mutation (Figure 2, A, B, and C). The maximal urine osmolality during treatment was observed for patient 3 (Figure 2), who had a urine osmolality of 248 during a diagnostic dDAVP infusion (32). To various extent, the treatment significantly decreased urinary output and increased urine osmolality in all patients. Plasma AVP levels were measured on day 1 (control), two times on day 2 (8:00 a.m. and 2:00 p.m.), and four times on day 3 (8:00 a.m., 2:00 p.m., 8:00 p.m., and 12:00 a.m.). Plasma AVP values were significantly different among patients (from 1.97 to 6.24 pg/ml; ANOVA, P < 0.05), but no significant differences among days or time effects were seen, and plasma values tended to decrease during the study (day 1, 5.39; day 2, 3.01, day 3, 3.34 pg/ml).
Longer treatment was tested for two patients who bore the R137H mutations. Reduced urine volumes and increased urine osmolalities were maintained for the 7 d of the treatment with SR49059 (Figure 3).
Cell Culture Studies
The effect of the nonpeptide V1a antagonist SR49059 was assessed on cell surface expression and function of two missense (R137H and W164S), one in-frame deletion (185_193del), and one nonsense (W284X) mutation. Immunofluorescence microscopy showed that under basal conditions, all V2 mutants were poorly expressed at the cell surface of transfected COS-1 cells (Figure 4A). A 16-h treatment with SR49059 increased the plasma membrane targeting of three of the V2 receptor mutants but not the nonsense mutant receptor. Figure 4B shows the quantitative assessment of the increase in cell surface expression for the 185_193del V2 receptor mutant using flow cytometry.
The increased cell surface expression of R137H, W164S, and 185_193del V2 receptor mutants after treatment with SR49059 resulted in a significant potentiation of the AVP-mediated cAMP production, suggesting that SR49059 restored function by acting as a pharmacologic chaperone. In contrast, the SR49059 treatment had no effect on AVP-stimulated cAMP accumulation in cells that expressed W284X V2 receptors (Figure 5A).
Kinetic analysis of the effect of SR49059 on the function of one of the V2 mutant receptors (185_193del) in HEK 293 cells is shown in Figure 5B. The potentiation effect peaked at 2 h after treatment but was maintained for at least 12 h after the antagonist. The relatively slow onset of the effect is consistent with the notion that the drug acts by favoring folding and cell surface trafficking of newly synthesized receptors (36). The modest increase in AVP-stimulated cAMP production that was observed in cells during the course of the experiment most likely reflects accumulation of a small number of 185_193del V2 mutant receptors at the cell surface.
Because the clinical development of SR49059 was interrupted (vide infra), we also tested the ability of YM087, a dual V1a and V2 vasopressin receptor antagonist (27), to rescue cell surface expression and function of 19 naturally occurring V2R mutants in COS-1 cells. As shown in Figure 6, YM087 promoted cell surface expression and potentiated AVP-mediated cAMP production for 10 naturally occurring mutations tested. As was the case for SR49059, YM087 had no effect on the nonsense mutations selected as negative controls: W284X (Figure 6), W71X, S167X, Q180X, and R337X (data not shown).
To date, no specific treatment that is aimed at restoring the function of the mutant V2 receptor is available to treat patients with X-linked NDI. Volume contraction and thiazide diuretics, amiloride, and indomethacin are acting only indirectly by decreasing the amount of tubular fluid presented to the distal tubule (37,38). These indirect forms of treatment are most effective in patients who have mild to moderate forms of X-linked NDI and bear incomplete loss-of-function mutations. These patients with mild to moderate disease are rare, and most patients are completely unresponsive to AVP or dDAVP (32). Here, we present evidence that nonpeptide vasopressin antagonists are potential specific treatments of this disease. It has been argued that the diversity of mutations in NDI may complicate the search for a universal therapeutic strategy for these patients (39). However, because approximately 50% of all NDI mutations are missense, a pharmacologic chaperone-based therapy could represent a potential general treatment of this protein-misfolding disease.
Manning et al. (40) designed in the 1970s numerous vasopressin and oxytocin receptor agonists and antagonists. Their clinical use in humans, however, was deceptive because antagonists in rats were found to be agonists in humans. This was found later to be due to different molecular structures of the receptors that are responsible for different affinities for agonists and antagonists in human and rat species (41). The random screening of chemical compounds resulted in the development of oral nonpeptide vasopressin receptor antagonists now called “Vaptans,” Vap for vasopressin, tan for antagonists (42). The structure of these compounds imitates the structure of the native hormone AVP, and these antagonists interfere with the binding pocket of AVP (43). During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 [Relcovaptan]), V2 (OPC-31260, OPC-41061 [Tolvaptan], VPA-985 [Lixivaptan], SR121463A and B, VP-343, and FR-161282), and mixed V1a/V2 (YM-087 [Conivaptan], JTV-605, and CL-385004) receptor antagonists have been studied intensively in various animal models and have reached phase III clinical trials for some of them (44).
We gave SR49059, a potent and selective, orally active, nonpeptide V1a receptor antagonist to five patients with V2 receptor defects. Previous in vitro binding experiments of human V1a receptors obtained from platelets, adrenals, aortic smooth muscles, and nonpregnant myometrium demonstrated that SR49059 was a selective V1a antagonist with inhibition constants (Ki) ranging from 1.5 to 6.5 nM (21). SR49059 displayed competitive nanomolar affinity for V1a receptors but weak affinities for human and nonhuman V2, V1b, and oxytocin receptors with Ki ranging from 220 to 1080 nM (21).
The absolute bioavailability of the nonmicronized formulation F1 used in this study was low and variable (5.3 ± 4.7%) with a Tmax of approximately 3 h and a terminal half-life of approximately 23 h. A 300-mg dose of the F1 formulation was reported in the Clinical Investigator Brochure to increase plasma concentration to 18.5 ng (33.5 micromolar, MW of SR49059 is 620.5) 3 h after the administration of SR49059 to normal volunteers. In our in vitro studies, a 16-h pretreatment with 10 micromolar (10−5 M) concentration of SR49059 or YM087 (MW 535.04) rescued cell surface expression and cAMP production.
Because in our clinical studies the maximal urine osmolality was observed, in general, 2 to 3 h after the oral administration of 300 mg of SR49059, these in vivo and in vitro results agree with these pharmacokinetics data. We demonstrated that SR49059, a V1a receptor antagonist that shows moderate affinity for the V2 receptor (275 nM) (21), rescued plasma membranes and signaling of the R137H, W164S, and 185_193del mutants, a confirmation of previous results obtained with the selective V2 receptor antagonists SR121463A, SR121463B, and VPA-985 (18,33) and other mutant V2 receptors (19,20). It is hypothesized that these compounds will enter the cell and the endoplasmic reticulum compartment and may stabilize the misfolded mutant receptor to a conformation that will permit further maturation through the endoplasmic reticulum and Golgi compartments. These nonpeptide vasopressin antagonists, with different affinities for V1 or V2 receptors, may be seen as a mold on which the unstable mutant receptor will wrap itself, perhaps hiding its hydrophobic residues and decreasing free energy (2). In recent in vitro results (45), we demonstrated that in vitro treatment with SR121463 for 16 h led to an important decrease in the polyubiquitination immunoreactive signal, indicating that the increased receptor maturation is accompanied by a decrease in the proportion of receptor being targeted to the polyubiquitination-dependent degradation pathway.
In five patients who had X-linked NDI and harbored three different AVPR2 mutations, SR49059 had beneficial effects on urine volume and osmolality starting a few hours after administration. This lag in efficacy is compatible with our previous in vitro observations (18), demonstrating that the pharmacologic chaperones need to permeate the cell and favor folding and trafficking of functional mutant receptors to the cell surface to be active. That nonsense mutations could not be rescued by the antagonist treatment is consistent with such a proposed mode of action. In a recent study, we demonstrated that the β-arrestin–mediated constitutive endocytosis of the V2 receptor (46) is not affected by SR49059 (33). The functional rescue observed in vitro and in our clinical study thus is unlikely to result from a stabilization of the V2 receptor at the cell surface.
Urine osmolality increased by 50% on day 3 from 2:00 p.m. to 8:00 p.m., and a maximum urine osmolality of 430 mOsm/kg (Figure 2A) was documented in patient 3, who was able to increase his urine osmolality only to 248 mOsm/kg during a previous dDAVP infusion (32). The urine osmolality changes were not secondary to increased endogenous plasma AVP concentrations. The effects on urine concentration occurred with no change in BP or pulse, an observation consistent with the lack of hemodynamic effect observed in hypertensive patients after the administration of 300 mg of SR49059 (22). The excretion of tonomoles being constant (Table 1), doubling urine osmolality will half the urine output. In patients with a mean urinary output of 12 L/d, a theoretical decrease of urine volume to 6 L/d could be obtained provided that a sustained drug effect could be reached through optimization of the drug regimen. A nonsignificant decrease in sodium excretion was observed, possibly indicating that these patients were not strictly in Na+ balance and/or pointing to the possible restoration of an AVP antinatriuretic effect (47). The highest increase in urine osmolality and consequent decrease in urine volume was observed with patient 3 with a maximal increase in urine osmolality after dDAVP of 248 mOsm/kg. Further clinical studies will needed to test whether the ability to rescue will depend on basal receptor function.
The proof-of-principle results obtained in this study indicate that pharmacologic chaperone-based therapy could be applied to other missense mutations or in-frame deletions or insertions that are responsible for X-linked NDI. Among the 207 families who had X-linked NDI and were referred to our laboratory (48; unpublished data), 66 of the 155 different putative disease–causing mutations are missense mutations that potentially are amenable to rescue by these pharmacologic chaperones.
Unfortunately, the clinical development of SR49059 has been interrupted during the course of these studies as a result of possible interference with the cytochrome P450 metabolic pathway. We would have liked to administer SR49059 to other patients with congenital NDI caused by a noncorrectable defect such as nonsense V2 receptor mutants or aquaporin mutants, but this was not possible. We also wanted to test whether other vasopressin antagonists, which could be clinically developed, may also act as pharmacologic chaperones for NDI-causing mutations. Another nonpeptide vasopressin receptor antagonist that is in advanced clinical testing phase and has an excellent safety profile for another application (27), YM087, was found to rescue cell surface expression and function of nine missense V2 mutant receptors. This provides supporting data that will allow us and others to test this compound and additional vasopressin ligands, including nonpeptide vasopressin agonists in patients with X-linked NDI, when they become available for such trials.
In addition to be a promising avenue for the treatment of X-linked NDI, stabilization of protein conformation, using small cell–permeable ligands, may represent a generally applicable rescue strategy for different diseases resulting from improper protein folding and targeting. These diseases include cystic fibrosis, osteogenesis imperfecta, α1-antitrypsin deficiency, NDI caused by mutations in AQP2, Gitelman syndrome, Fabry disease, and many others (49–58).
This study was supported by grants MOP 8126 from the Canadian Institutes of Health Research (D.G.B.) and the Kidney Foundation of Canada (D.G.B. and M.B.) and la Fondation J. Rodolphe-La Haye (D.G.B.). J.P.M. was supported by a studentship from the MRC/PMAC Health Program. V.B. was supported by a studentship from the Quebec Society of Hypertension, the Heart and Stroke Foundation of Canada, and the Fonds de Recherche en Sante[Combining Acute Accent] du Que[Combining Acute Accent]bec. A.S. was supported by a studentship from the Canadian Institute for Health Research. M.B. holds a Canada Research Chair in Signal Transduction and Pharmacology, and D.G.B. holds a Canada Research Chair of Kidney Disease.
We thank C. Serradeil-LeGal (Sanofi-Aventis) and R.E. Desjardins (Yamanouchi Pharma America, Inc., Paramus, NJ) for the generous gift of SR49059 and YM087, respectively; L. Cournoyer and S. Se[Combining Acute Accent]ne[Combining Acute Accent]chal for technical assistance; M. Moreau for assistance with the figures; T.M. Fujiwara for critical reading of the manuscript; and D. Binette for graphical and secretarial expertise. We also thank Dr. M. Caron for providing the R137H construction and Dr. F. Madore for statistical advice.
Published online ahead of print. Publication date available at www.jasn.org
V.B. and J.-P.M. contributed equally to this work.
1. Carrell RW, Lomas DA: Conformational disease. Lancet350 :134 –138,1997
2. Cohen FE, Kelly JW: Therapeutic approaches to protein-misfolding diseases. Nature426 :905 –909,2003
3. Bichet DG, Fujiwara TM: Nephrogenic diabetes insipidus. In: The Metabolic and Molecular Bases of Inherited Disease, 8th Ed., edited by Scriver CR, Beaudet AL, Sly WS, Vallee D, Childs B, Kinzler KW, Vogelstein B, New York, McGraw-Hill,2001 , pp4181 –4204
4. Fujiwara TM, Bichet DG: Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol16 :2836 –2846,2005
5. Tsukaguchi H, Matsubara H, Taketani S, Mori Y, Seido T, Inada M: Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus. J Clin Invest96 :2043 –2050,1995
6. Schoneberg T, Yun J, Wenkert D, Wess J: Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a coexpressed receptor polypeptide. EMBO J15 :1283 –1291,1996
7. Wenkert D, Schoneberg T, Merendino JJ Jr, Rodriguez Pena MS, Vinitsky R, Goldsmith PK, Wess J, Spiegel AM: Functional characterization of five V2 vasopressin receptor gene mutations. Mol Cell Endocrinol124 :43 –50,1996
8. Oksche A, Schulein R, Rutz C, Liebenhoff U, Dickson J, Muller H, Birnbaumer M, Rosenthal W: Vasopressin V2 receptor mutants that cause X-linked nephrogenic diabetes insipidus: Analysis of expression, processing, and function. Mol Pharmacol50 :820 –828,1996
9. Sadeghi H, Robertson GL, Bichet DG, Innamorati G, Birnbaumer M: Biochemical basis of partial NDI phenotypes. Mol Endocrinol11 :1806 –1813,1997
10. Ala Y, Morin D, Mouillac B, Sabatier N, Vargas R, Cotte N, Dechaux M, Antignac C, Arthus M-F, Lonergan M, Turner MS, Balestre M-N, Alonso G, Hibert M, Barberis C, Hendy GN, Bichet DG, Jard S: Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: Molecular basis of a mild clinical phenotype. J Am Soc Nephrol9 :1861 –1872,1998
11. Pasel K, Schulz A, Timmermann K, Linnemann K, Hoeltzenbein M, Jaaskelainen J, Gruters A, Filler G, Schoneberg T: Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. J Clin Endocrinol Metab85 :1703 –1710,2000
12. Morello J-P, Bichet DG: Nephrogenic diabetes insipidus. Annu Rev Physiol63 :607 –630,2001
13. Hermosilla R, Oueslati M, Donalies U, Schonenberger E, Krause E, Oksche A, Rosenthal W, Schulein R: Disease-causing V(2) vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic5 :993 –1005,2004
14. Robben JH, Knoers NV, Deen PM: Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model. Am J Physiol Renal Physiol289 :F265 –F272,2005
15. Crawford JD, Bode HH: Disorders of the posterior pituitary in children. In: Endocrine and Genetic Diseases of Childhood and Adolescence, 2nd Ed., edited by Gardner LI, Philadelphia, W.B. Saunders,1975 , pp126 –158
16. van Lieburg AF, Knoers NVAM, Monnens LAH: Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol10 :1958 –1964,1999
17. Earley L, Orloff J: The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patient with vasopressin-resistant diabetes insipidus. J Clin Invest41 :1988 –1997,1962
18. Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus M-F, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M: Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest105 :887 –895,2000
19. Tan CM, Nickols HH, Limbird LE: Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J Biol Chem278 :35678 –35686,2003
20. Wuller S, Wiesner B, Loffler A, Furkert J, Krause G, Hermosilla R, Schaefer M, Schulein R, Rosenthal W, Oksche A: Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem279 :47254 –47263,2004
21. Serradeil-Le Gal C, Wagnon J, Garcia C, Lacour C, Guiraudou P, Christophe B, Villanova G, Nisato D, Maffrand JP, Le Fur G, et al.: Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. J Clin Invest92 :224 –231,1993
22. Thibonnier M, Kilani A, Rahman M, DiBlasi TP, Warner K, Smith MC, Leenhardt AF, Brouard R: Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients. Hypertension34 :1293 –1300,1999
23. Akerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M: Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol106 :1047 –1053,1999
24. Hayoz D, Bizzini G, Noel B, Depairon M, Burnier M, Fauveau C, Rouillon A, Brouard R, Brunner HR: Effect of SR 49059, a V1a vasopressin receptor antagonist, in Raynaud’s phenomenon. Rheumatology (Oxford)39 :1132 –1138,2000
25. Tahara A, Saito M, Sugimoto T, Tomura Y, Wada K, Kusayama T, Tsukada J, Ishii N, Yatsu T, Uchida W, Tanaka A: Pharmacological characterization of YM087, a potent, nonpeptide human vasopressin V1a and V2 receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol357 :63 –69,1998
26. Decaux G: Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med110 :582 –584,2001
27. Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I, Ghali JK, Selaru P, Chanoine F, Pressler ML, Konstam MA: Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in patient with advanced heart failure. Circulation104 :2417 –2423,2001
28. Martinez-Castelao A: Conivaptan (Yamanouchi). Curr Opin Investig Drugs3 :89 –95,2002
29. Doggrell SA: Conivaptan Yamanouchi. Curr Opin Investig Drugs6 :317 –326,2005
30. Bichet DG, Arthus M-F, Lonergan M, Hendy GN, Paradis AJ, Fujiwara TM, Morgan K, Gregory MC, Rosenthal W, Didwania A, Antaramian A, Birnbaumer M: X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest92 :1262 –1268,1993
31. Bichet DG, Birnbaumer M, Lonergan M, Arthus M-F, Rosenthal W, Goodyer P, Nivet H, Benoit S, Giampietro P, Simonetti S, Fish A, Whitley CB, Jaeger P, Gertner J, New M, DiBona FJ, Kaplan BS, Robertson GL, Hendy GN, Fujiwara TM, Morgan K: Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet55 :278 –286,1994
32. Bichet DG, Razi M, Lonergan M, Arthus M-F, Papukna V, Kortas C, Barjon JN: Hemodynamic and coagulation responses to 1-desamino[8-D-arginine]vasopressin (dDAVP) infusion in patients with congenital nephrogenic diabetes insipidus. N Engl J Med318 :881 –887,1988
33. Bernier V, Lagace M, Lonergan M, Arthus MF, Bichet DG, Bouvier M: Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol18 :2074 –2084,2004
34. Wong YH, Federman A, Pace AM, Zachary I, Evans T, Pouyssegur J, Bourne HR: Mutant alpha subunits of Gi2 inhibit cyclic AMP accumulation. Nature351 :63 –65,1991
35. Bichet DG, Arthus M-F, Barjon JN, Lonergan M, Kortas C: Human platelet fraction arginine-vasopressin. J Clin Invest79 :881 –887,1987
36. Petaja-Repo UE, Hogue M, Bhalla S, Laperriere A, Morello JP, Bouvier M: Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation. EMBO J21 :1628 –1637,2002
37. Hebert SC: Molecular mechanisms. Semin Nephrol19 :504 –523,1999
38. Knoers NV, Monnens LL: Nephrogenic diabetes insipidus. Semin Nephrol19 :344 –352,1999
39. Oksche A, Rosenthal W: The molecular basis of nephrogenic diabetes insipidus. J Mol Med76 :326 –337,1998
40. Thibonnier M, Coles P, Thibonnier A, Shoham M: The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol41 :175 –202,2001
41. Oksche A, Leder G, Valet S, Platzer M, Hasse K, Geist S, Krause G, Rosenthal A, Rosenthal W: Variant amino acids in the extracellular loops of murine and human vasopressin V2 receptors account for differences in cell surface expression and ligand affinity. Mol Endocrinol16 :799 –813,2002
42. Francis GS, Tang WH: Vasopressin receptor antagonists: Will the “vaptans” fulfill their promise? JAMA291 :2017 –2018,2004
43. Mouillac B, Chini B, Balestre MN, Elands J, Trumpp-Kallmeyer S, Hoflack J, Hibert M, Jard S, Barberis C: The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem270 :25771 –25777,1995
44. Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G: Nonpeptide vasopressin receptor antagonists: Development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res139 :197 –210,2002
45. Bernier V, Pontier SM, Charest PG, Perroy J, Bichet DG, Bouvier M: Action mechanisms of pharmacological chaperones acting on the V2 vasopressin receptor [Abstract]. Clin Exp Pharmacol Physiol31 :A185 ,2004
46. Barak LS, Oakley RH, Laporte SA, Caron MG: Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A98 :93 –98,2001
47. Bankir L, Fernandes S, Bardoux P, Bouby N, Bichet DG: Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans. J Am Soc Nephrol16 :1920 –1928,2005
48. Arthus M-F, Lonergan M, Crumley MJ, Naumova AK, Morin D, De Marco L, Kaplan BS, Robertson GL, Sasaki S, Morgan K, Bichet DG, Fujiwara TM: Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol11 :1044 –1054,2000
49. Kuznetsov G, Nigam SK: Folding of secretory and membrane proteins. N Engl J Med339 :1688 –1695,1998
50. Burrows JA, Willis LK, Perlmutter DH: Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA97 :1796 –1801,2000
51. Fan JQ, Ishii S, Asano N, Suzuki Y: Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med5 :112 –115,1999
52. Rubenstein RC, Zeitlin PL: A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: Partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med157 :484 –490,1998
53. Marr N, Bichet DG, Hoefs S, Savelkoul PJM, Konings IBM, De Mattia F, Graat MPJ, Arthus M-F, Lonergan M, Fujiwara M, Knoers NVAM, Landau D, Balfe WJ, Oksche A, Rosenthal W, Muller D, van Os CH, Deen PMT: Cell-biologic and functional analyses of five new aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus. J Am Soc Nephrol13 :2267 –2277,2002
54. De Jong JC, Van Der Vliet WA, Van Den Heuvel LP, Willems PH, Knoers NV, Bindels RJ: Functional expression of mutations in the human NaCl cotransporter: Evidence for impaired routing mechanisms in Gitelman’s syndrome. J Am Soc Nephrol13 :1442 –1448,2002
55. Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP, Knoers NV: Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit. Nat Genet26 :265 –266,2000
56. Bradbury J: Chaperones: Keeping a close eye on protein folding. Lancet361 :1194 –1195,2003
57. Noorwez SM, Kuksa V, Imanishi Y, Zhu L, Filipek S, Palczewski K, Kaushal S: Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa. J Biol Chem278 :14442 –14450,2003
58. Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM: Pharmacologic rescue of conformationally-defective proteins: Implications for the treatment of human disease. Traffic5 :821 –837,2004