Potential of Nonpeptide (Ant)agonists to Rescue Vasopressin V2 Receptor Mutants for the Treatment of X-linked Nephrogenic Diabetes Insipidus

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1 Journal of Neuroendocrinology From Molecular to Translational Neurobiology REVIEW ARTICLE Journal of Neuroendocrinology, ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd otential of Nonpeptide (Ant)agonists to Rescue Vasopressin V Receptor Mutants for the Treatment of X-linked Nephrogenic Diabetes Insipidus E. L. Los,. M. T. Deen and J. H. Robben Department of physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Journal of Neuroendocrinology Correspondence to: Joris H. Robben, 86 Deptartment of hysiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ( j.robben@fysiol.umcn.nl). According to the body s need, water is reabsorbed from the pro-urine that is formed by ultrafiltration in the kidney. This process is regulated by the antidiuretic hormone arginine-vasopressin (AV), which binds to its type receptor (VR) in the kidney. Mutations in the gene encoding the VR often lead to the X-linked inheritable form of nephrogenic diabetes insipidus (NDI), a disorder in which patients are unable to concentrate their urine despite the presence of AV. Many of these mutations are missense mutations that do not interfere with the intrinsic functionality of VR, but cause its retention in the endoplasmic reticulum (ER), making it unavailable for AV binding. Because the current treatments for NDI relieve its symptoms to some extent, but do not cure the disorder, cell-permeable antagonists (pharmacological chaperones) have been successfully used to stabilise the mutant receptors and restore their plasma membrane localisation. Recently, cell-permeable agonists also were shown to rescue ER-retained VR mutants, leading to increased cam levels and translocation of aquaporin- to the apical membrane. This makes VR-specific cell-permeable agonists very promising therapeutics for NDI as a result of misfolded VR receptors. Key words: vasopressin, receptors, membrane nuclear. doi: /j x Human osmoregulation Maintaining the water homeostasis of the body is crucial for its proper functioning. Accordingly, water and electrolytes are balanced by a carefully orchestrated interplay between volume- and osmoregulation that is regulated by multiple hormones. A key hormone in process is the antidiuretic hormone arginine-vasopressin (AV), which is released from the pituitary in states of hypernatreamia or hypovolaemia (1, ). The main target organ of AV in the process of osmoregulation is the kidney, which is composed of approximately one million nephrons, the functional units in kidney. In these nephrons, ultrafiltration results in the formation of a daily volume of approximately 180 l of pro-urine. Of this large volume, approximately 99% of the water is reabsorbed by the tubular epithelial cells of the nephron, whereas only 1.5 l of water is excreted via the urine. Approximately 90% of the tubular water reabsorption occurs in the proximal tubules and descending loop of Henle, where water is reabsorbed iso-osmotically via the water channel aquaporin-1. The remaining 9% can be reabsorbed in the principal cells of the collecting duct, the final part of the nephron, and is regulated by AV. Binding of AV to its type receptor on the basolateral (interstitial) side of the principal cells induces a cam cascade that increases protein levels of the water channel aquaporin- (AQ) and triggers the protein kinase A-induced translocation of AQ storage vesicles to the apical (luminal) plasma membrane (Fig. 1A) (1). Insertion of AQ in this membrane facilitates its water permeability and allows water transport from the tubular lumen into the principal cells, and its subsequent flow into the interstitium via the water channels aquaporin-3 and 4 in the basolateral plasma membrane. Together, this allows the body to retain water and compensate for states of hypernatraemia or hypovolaemia. When the water balance is restored, AV release will lead to decreased plasma AV levels and thereby to the retrieval of AQ from the apical membrane, rendering the collecting duct impermeable to water (1). Disturbances in the above process will result in diabetes insipidus (DI), a disease characterised by polyuria and compensatory polydipsia. The underlying causes of DI are diverse and can be a central defect, in which no functional AV is released from the pituitary, or may be caused by defects in the kidney (nephrogenic DI, NDI). Four

2 394 E. L. Los et al. (A) AQ3 AQ4 AQ AV V R Gsγ Gsβ Gsα AC Basolateral (B) interstitial cam KA AT Apical luminal AQ3 AQ4 V R AQ H O AV AQ Fig. 1. Transcellular water transport in renal collecting principal duct cells and molecular cause of X-linked nephrogenic diabetes insipidus (NDI) (A) Vasopressin binding to its type receptor (VR) triggers a cam cascade that leads to the insertion of aquaporin- (AQ) water channels in the apical membrane. This allows water to pass through this membrane and transcellular water transport to realise concentration of the pro-urine and thereby antidiuresis. (B) In the X-linked form, NDI is often caused by VR class II mutants trapped in the endoplasmic reticulum as a result of their misfolding, making them unavailable for binding arginine-vasopressin (AV) at the basolateral plasma membrane. As a result, no transcellular water transport takes place, leading to polyuria. KA, protein kinase A. different types of NDI are known. First, acquired NDI can originate as a side-effect of drugs, with the most prominent being the antibipolar drug lithium. Second and third, autosomal recessive and dominant inheritable NDI is caused by gene mutations in the AQ gene (3, 4). Finally, mutations in the AVR gene, which encodes VR, is the cause of the X-linked inheritable form of NDI (Fig. 1B) (5, 6). Over recent years, much progress has been made with respect to resolving the molecular defect that causes X-linked NDI and, because promising approaches have been undertaken to identify potential cures for this most prominent form of NDI, these will be reviewed here. The other types of NDI have recently been reviewed elsewhere (1, 7, 8). Clinical phenotype and current treatment NDI is characterised by the kidney s inability to concentrate the pro-urine in response to AV. As a consequence, untreated adult patients may have a daily output of 15 0 l of highly dilute (usually < 100 mosmol kg) urine. In newborn infants, NDI may manifest itself as irritability, poor feeding, poor weight gain and dehydration symptoms, such as dryness of the skin, loss of skin turgor, recessed eyeballs depression of the anterior fontanel and a scaphoid abdomen. When left untreated, young patients show failure to thrive and reduced growth, most likely as a result of feeding problems, ingestion of high amounts of water or repeated episodes of dehydration. In addition, repeated periods of hypernatraemic dehydration may result in permanent brain damage, mental retardation and or developmental delay (7, 9). Classically, the diagnosis NDI was made after a dehydration test, followed by administration of the synthetic AV analogue 1-desamino-8-D-AV (ddav). All patients suffering from NDI will not be able to concentrate their urine to values beyond 00 mosm, whereas patients suffering from central DI will show a response to ddav administration. In patients with acquired NDI, often as a result of chronic lithium treatment for bipolar disorder, the urine concentrating defect is caused by a down-regulation of AQ (10) and a loss of the water-transporting principal cells of the collecting duct (11). However, these patients have some residual concentrating capacity, allowing them to concentrate their urine > 00 mosm when challenged in a dehydration test or upon administration of ddav. ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,

3 (Ant)agonists to rescue of VR mutants 395 Besides their distinct patterns of inheritance, X-linked and autosomal inheritable NDI can be discriminated by the presence or absence of an extrarenal response. Further to its role in the kidney, the VR also triggers the release of von Willebrand factor, factor VIII and tissue-type plasminogen factor. Therefore, in patients with mutations in the AQ gene, plasma levels of the above factors can be measured when a ddav challenge is performed, whereas patients suffering from the X-linked form, in which the VR is not functional, will fail to show this extrarenal response (7, 9). Currently, if a family history of NDI is known, gene sequencing is the method of choice to determine the presence of a mutation in the AVR or AQ genes in a fast, reliable and stress-free manner. The main and most obvious treatment for NDI patients is the replacement of urinary water losses by a sufficient supply of fluid, combined with a low-solute diet to reduce the renal osmolar load and thus decrease the mandatory water excretion. The diuretic hydrochlorothiazide, combined with a second diuretic amiloride or the cyclooxygenase inhibitor indomethacin, has been proven effective to reduce the urine output of NDI patients by up to 50%. Treatment with these diuretics decreases the distal tubular sodium transport, thereby leading to hypovolaemia. To compensate for this, the renin angiotensin aldosterone system will be activated, resulting in increased angiotensin II-mediated sodium reabsorption in the proximal tubules of the nephron. Because water transport in this segment follows sodium uptake iso-osmotically via AQ1, this will lead to an increased reabsorption of water, thereby reducing the amount of water delivered to the distal nephron (1, 13). Treatment with diuretics, however, may affect the delicate sodium balance in NDI patients, and therefore require close monitoring of the serum osmolality when treatment is started. Misfolding of VR causes X-linked nephrogenic diabetes insipidus To date, over 00 mutations have been described in the AVR gene ( which can be categorised into five classes according to their cellular fate (8). Briefly, class I mutations result in premature stop codons or unstable RNA. Class II comprises the missense mutations that lead to endoplasmic reticulum (ER)-retention of full-length receptors. Class III and IV mutations are defect in Gs protein or AV binding, respectively, whereas class V mutations result in trafficking defects beyond the early secretory pathway. These classes and examples of VR mutations that have been categorised this way have been reviewed elsewhere (8, 14). Of these five classes, class II is the most prevalent one, comprising approximately 45% of all mutations, and the missense mutations of this class often affect only one amino acid in the whole receptor (15). The misfolding resulting from such a class II mutation may therefore not necessarily impair the intrinsic functionality of the receptor. Indeed, rather than inhibiting receptor function, overexpression studies by us (16) and others (17 19) have shown that approximately 60 70% of class II VR mutants are intrinsically functional as determined by over-expression experiments. Therefore, rather than resulting in a nonfunctional protein (Class III or IV), the cell biological cause by which class II leads to the NDI phenotype is their retention in the ER (16) and or ER-Golgi intermediate compartment (0), rendering them inaccessible to AV, which cannot penetrate the plasma membrane (Fig. 1B). Rescue of VR mutants by cell-permeable antagonists Identification of the molecular defects underlying NDI, combined with notion that most G protein-coupled receptors (GCRs) are normally functional at the plasma membrane, incited efforts to rescuing the plasma membrane localisation of class II VR mutants aiming to identify a novel and superior treatment for NDI. This has been attempted using chemical compounds that affect molecular chaperones (folding proteins), which are therefore referred to as chemical chaperones (1). To reduce cellular toxicity and increase specificity, cell-penetrating peptides () and cell-permeable antagonists (see below) have been used. In 000, the research groups of Dr Bichet and Dr Bouvier achieved a major breakthrough because they showed that ER-retained VR mutants can be stabilised by incubation with the nonpeptide cell-permeable antagonist SR11463 (17). After the entry of this compound into the cell and its binding to the mutant receptor, this compound stabilised the receptor s conformation (Fig., step 1). Analogous to ER-resident molecular chaperones, these cell-permeable antagonists are called pharmacological chaperones. As a result of their stabilisation, the receptor mutants are no longer recognised by the ER quality control mechanism as being misfolded, which allows them to exit the ER (Fig., step ), achieve mature glycosylation in the Golgi compartment and be inserted into the plasma membrane (Fig., step 3). It was shown that subsequent plasma membrane rescue does not interfere with proper targeting of the newly matured receptors because these were translocated to the basolateral plasma membrane of polarised renal cells, leading to a similar localisation as found for the wild-type receptor (1, 3). To determine which antagonist is the most ideal compound to restore NDI in patients, other VR-binding antagonists were characterised to optimise the plasma membrane rescue and subsequent activation of the receptor. Rescue of specific mutants may depend on the compound used because it was shown that the V1aR antagonist SR49059 (which acts as a weak antagonist on the VR) is able to rescue the VR mutants K100D, C319Y (19) and R137H (4), whereas it could not rescue the mutants del6-64, D136A, 3S, W33H and F38H, which are all close to the cytoplasmic ends of the respective transmembrane domains in which they are present (19). By contrast, the VR antagonist SR11463 was able to efficiently rescue the plasma membrane expression of all of these mutants. Moreover, four mutants at the interface of transmembrane domains II and IV were insensitive to rescue by either of these antagonists. Thus, the location of the mutation in the receptor determines whether it can be rescued (19). An overview of the above data is shown in Table 1. A second determinant for the efficiency of rescue is the affinity of the antagonist for the receptor. From low to high affinity, the V1aR antagonist SR49059, or the VR antagonists OC3160, OC41061 and SR11463, showed an increased ability to restore ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,

4 396 E. L. Los et al. 1 AQ3 AQ4 4 V R 3 Basolateral interstitial Apical luminal Fig.. Rescue of plasma membrane expression of vasopressin type receptor (VR) mutants in nephrogenic diabetes insipidus. (1) Cell-permeable antagonists can enter the cell to bind class II mutant VR in the endoplasmic reticulum (ER) and stabilise their conformation. () This allows the mutant protein to leave the ER and (3) mature in the Golgi compartment, which facilitates its rescue to the plasma membrane. (4) There, sufficiently high levels of arginine-vasopressin can displace the antagonist to activate the mutant receptor. the plasma membrane localisation of eight ER-retained mutants. Furthermore, plasma membrane rescue and its corresponding maturation demonstrated a positive correlation with the concentration in which the compounds were applied (5). On the basis of the latter two determinants, applying a high concentration of a highaffinity antagonist would be the method of choice for the treatment of patients. However, once the antagonist-bound receptor reaches the plasma membrane, it requires displacement by AV or its synthetic analogue ddav to allow activation of the receptor (Fig., step 4). At high concentrations, the low-affinity antagonist SR49059 showed optimal rescue, most likely as a result of its easy displacement by ddav, whereas high-affinity antagonists failed to show efficient displacement, despite recruiting high amounts of mutant receptor to the plasma membrane. However, at clinically feasible concentrations (< 30 nm) (18), the VR antagonists OC3160 and OC41061 could be displaced by ddav, allowing functional rescue (5). Therefore, we consider that the most efficient overall functional rescue is a balance between the ability of a compound to promote the mutant receptor s trafficking to the plasma membrane, and its ability to be displaced by a natural or synthetic agonist there. Nonpeptide antagonists as a treatment for NDI Currently, only one clinical trial has been conducted to test the efficiency of cell-permeable antagonists, in which five patients with mutations in the AVR gene (three encoding the mutation R137H, one encoding W164S and one the del6-64 mutation) were treated with SR49059 (Relcovaptan). atients were administered three oral doses daily for two consecutive days. Although there was some variation in the responses between patients, an average reduction of the 4-h urine volume (from 11.9 to 8. l day), combined with an increased 4-h urine osmolality (from approximately 100 to 150 mosm kg) and reduced water intake ( l day), was observed (18). In a subsequent 7-day trial, one patient showed a maximum urine osmolality of approximately 450 mosm, approximately two-fold higher than his baseline levels (18). Although this increased level is still far below the maximum concentrating ability of a healthy individual, it resulted in a 50% reduction in urine output and water consumption in this patient, clearly demonstrating that cell-permeable antagonists are promising compounds to relieve NDI in patients and improve their quality of life. Because of potential interference with the cytochrome 450 metabolic pathway, however, the trial with SR49059 had to be discontinued. Recently, the cell-permeable antagonist OC41061 (Tolvaptan) has been approved in the USA and Europe for the treatment of hyponatraemia in the syndrome of inappropriate antidiuretic hormone secretion and congestive heart failure (6, 7). This positive safety assessment, together with OC41061 being an efficient pharmacological chaperone at clinically feasible concentrations, paves the road for clinical trials to test the potential of Tolvaptan for treating NDI in the future. otential of nonpeptide agonists for the treatment of NDI The pharmaceutical industry has recently made efforts to develop nonpeptide VR-specific agonists for oral administration. Likely, their small-molecule composition and relatively high hydrophobicity allows them to pass cell membranes, thereby facilitating an improved uptake by the intestinal tract compared to classical peptide-based agonists such as ddav. Recently, we demonstrated that a recently-developed nonpeptide VR agonist, OC51803 and the two novel nonpeptide agonists, VA and VA999089, were able ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,

5 (Ant)agonists to rescue of VR mutants 397 Table 1. Overview of lasma Membrane and or Functional Rescue of Type Vasopressin Receptor Mutants in Nephrogenic Diabetes Insipidus. Compound (Ant)agonists Specificity lasma membrane rescue Functional rescue Reference SR49059 Antagonist V1R R137H R137H 4 S167T, C319Y C319Y, S167T 19 L44, D6 64, R113W, I130F, S167T, G01D, T04N, V06D L44, I130F, S167T 5 YM087 Antagonist V1RA R L59, D6 64, L83Q, Y18S, R137H, W164S, D165D, S167L, A94, 3H, W84X All 18 SR11463 Antagonist VR L59, D6 64, L83Q, Y18S, S167L, All 17 A94, 3H, R337stop DV78, L9, R337X Not determined 3 L44, D6 64, R113W, I130F, S167T, None 5 G01D, T04N, V06D D6 64, S167T, C319Y, 3S, W33H None 19 VA985 Antagonist VR L59, D6 64, L83Q, Y18S, S167L, A94, 3H, R337stop OC41061 Antagonist VR L44, D6 64, R113W, I130F, S167T, OC3160 G01D, T04N, V06D All 17 L44, I130F, S167T 5 VA Agonist VR None L44, Y18S, I130F, 8 VA OC51803 MCF14 Agonist VR L44, A94, R337X S167T, Y80C, 3S L44, A94, R337X* 9 MCF18 MCF57 The compound name, nature and highest specificity for a subtype of vasopressin receptor are indicated. Furthermore, those mutants positively tested to be rescued from the endoplasmic reticulum to the plasma membrane, together with whether their function was restored, are shown. *R337X could not directly be activated by the MCF compounds, but only after plasma membrane rescue and subsequent stimulation with 1-desamino-8-D-AV. AQ3 AQ4 AC KA cam Basolateral interstitial Apical luminal Fig. 3. roposed mechanism of intracellular activation of class II vasopressin type receptor (VR) mutants. Similar to cell-permeable antagonists, cell-permeable agonists are able to bind VR mutants in the endoplasmic reticulum. Rather than stabilising their conformation, these agonists directly activate these intracellularly-located receptors by signaling to pre-formed receptor-g protein-adenylate cyclase (AC) complexes. The resulting cam response will then activate protein kinase A (KA) to induce trafficking of aquaporin- (AQ) storage vesicles to, and their fusion with, the apical membrane, thereby restoring the NDI phenotype. ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,

6 398 E. L. Los et al. to functionally rescue ER-retained VR mutants in polarised renal cells. The agonists were able to induce a cam response, eventually leading to an increase in translocation of AQ to the apical cell membrane (Fig. 3) in six out of seven VR mutants (L44, Y18S, I130F, S167T, Y80C and 3S, but not S167L). Importantly, the non-cell-permeable peptide agonists ddav did not induce signalling for any of these mutants, indicating that entry into the cell is critical for receptor activation. Moreover, incubation with the nonpeptide agonists did not affect ER localisation for mutants, failed to induce receptor maturation, but resulted in a rapid cam response, indicating that the observed signal was derived from ERretained receptors. In addition, nonpeptide agonists did not increase degradation of intracellularly retained VR mutants (8). In addition, Jean-Alphonse et al. (9) revealed that three structurally related nonpeptide agonists (MCF14, MCF18 and MCF57) increased cam levels of intracellularly retained VR mutants L44 and A94, coinciding with an increased membrane expression and improved maturation of the VR mutants. Moreover, membrane rescued mutants were sensitive to AV, and thus functional. These latter MCF agonists also exhibited antagonistic effects on VR-dependent b-arrestin recruitment, internalisation and subsequent ERK activation, indicating an additional beneficial effect on VR signalling (9) Thus, the signalling and trafficking properties of the MCF agonists on the wild-type and mutant VR are different from the VA999088, VA and OC51803, as summarised in Table 1. This indicates that the compounds studied by Jean-Alphonse et al. (9) and ourselves may bind to different residues of the AV binding pocket of VR, which may explain the different mechanism of rescue. Alternatively, differences regarding the mechanism could also lie in the use of stably transfected polarised renal cells (MDCK cells) versus transiently transfected nonpolarised renal cells (tsa01 cells). In conclusion, the effect of nonpeptide agonists on VR mutants is mutation- and agonist-dependent, and studies clearly demonstrate the potential of cell-permeable VR agonists as future therapies for NDI as a result of misfolded VR mutants. Future perspectives The broad applicability of nonpeptide antagonists as pharmacological chaperones has been demonstrated because specific antagonists or allosteric modulators have been shown to rescue the plasma membrane expression of mutants of the GCRs rhodopsin (30), calcium-sensing receptor (31) and gonadotrophin-releasing hormone receptor (3, 33). Future clinical trials will determine whether these promising in vitro experiments can be extrapolated to a positive effect in patients and whether pharmacological chaperones are promising treatments for the conformational diseases resulting from misfolded receptors. Treatment with nonpeptide VR agonists, however, is likely superior over nonpeptide antagonists because rescue of cell surface expression and subsequent displacement by endogenous AV is circumvented. In addition, the assembly of a complete b-adrenergic receptor signalosome in the ER (34, 35), activation of the ER-localised GR30 by its naturally cell permeable agonist oestrogen (36) and intracellular activation of VR mutants by nonpeptide agonists (8) clearly show that GCRs normally functioning in the plasma membrane can generate a signalling cascade from an intracellular location. Thus, nonpeptide agonists appear to represent ideal therapeutics to treat not only NDI as a result of misfolded VR mutants, but also many other diseases as a result of misfolded and ERretained GCRs. Acknowledgements.M.T.D. is a recipient of VICI grant of the Netherlands Organization for Scientific research (NWO)..M.T.D. is supported by grants from the Dutch Kidney Foundation (C03-060), NWO ( ), Coordination Theme 1 (Health) of the European Community s 7th Framework rogram (HEALTH-F , entitled EUNEFRON) and the UMC St Radboud (004-55). Received: 13 January 010, revised 10 February 010, accepted 10 February 010 References 1 Boone M, Deen. hysiology and pathophysiology of the vasopressinregulated renal water reabsorption. flugers Arch 008; 456: Fenton RA, Knepper MA. Mouse models and the urinary concentrating mechanism in the new millennium. hysiol Rev 007; 87: Deen M, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, van Os CH, van Oost BA. Requirement of human renal water channel aquaporin- for vasopressin-dependent concentration of urine. Science 1994; 64: Mulders SM, Bichet DG, Rijss JL, Kamsteeg EJ, Arthus MF, Lonergan M, Fujiwara M, Morgan K, Leijendekker R, van der Sluijs, van Os CH, Deen MT. An aquaporin- water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J Clin Invest 1998; 10: Van den Ouweland AMW, Dreesen JCFM, Verdijk M, Knoers NVAM, Monnens LAH, Rocchi M, VanOost BA. Mutations in the vasopressin type- receptor gene (Avpr) associated with nephrogenic diabetes-insipidus. Nat Genet 199; : Rosenthal W, Seibold A, Antaramian A, Lonergan M, Arthus MF, Hendy GN, Birnbaumer M, Bichet DG. Molecular-identification of the gene responsible for congenital nephrogenic diabetes-insipidus. Nature 199; 359: Bichet DG. Nephrogenic diabetes insipidus. Adv Chronic Kidney Dis 006; 13: Robben JH, Knoers NVAM, Deen MT. Cell biological aspects of the vasopressin type- receptor and aquaporin water channel in nephrogenic diabetes insipidus. Am J hysiol Renal hysiol 006; 91: F57 F70. 9 Knoers NV, Monnens LL. Nephrogenic diabetes insipidus. Semin Nephrol 1999; 19: Marples D, Christensen S, Christensen EI, Ottosen D, Nielsen S. Lithiuminduced downregulation of aquaporin- water channel expression in rat kidney medulla. J Clin Invest 1995; 95: Christensen BM, Marples D, Kim YH, Wang W, Frokiaer J, Nielsen S. Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI. Am J hysiol Cell hysiol 004; 86: C95 C Shirley DG, Walter SJ, Laycock JF. The antidiuretic effect of chronic hydrochlorothiazide treatment in rats with diabetes insipidus: renal mechanisms. Clin Sci (Lond) 198; 63: ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,

7 (Ant)agonists to rescue of VR mutants Earley LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest 196; 41: Robben JH, Deen M. harmacological chaperones in nephrogenic diabetes insipidus: possibilities for clinical application. Biodrugs 007; 1: Bichet DG. Vasopressin receptor mutations in nephrogenic diabetes insipidus. Semin Nephrol 008; 8: Robben JH, Knoers NVAM, Deen MT. Characterization of vasopressin V receptor mutants in nephrogenic diabetes insipidus in a polarized cell model. Am J hysiol Renal hysiol 005; 89: F65 F7. 17 Morello J, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, etaja-repo U, Angers S, Morin D, Bichet DG, Bouvier M. harmacological chaperones rescue cell-surface expression and function of misfolded V vasopressin receptor mutants. J Clin Invest 000; 105: Bernier V, Morello J, Zarruk A, Debrand N, Salahpour A, Lonergan M, Arthus MF, Laperriere A, Brouard R, Bouvier M, Bichet DG. harmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 006; 17: Wuller S, Wiesner B, Loffler A, Furkert J, Krause G, Hermosilla R, Schaefer M, Schulein R, Rosenthal W, Oksche A. harmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V receptors. J Biol Chem 004; 79: Hermosilla R, Oueslati M, Donalies U, Schonenberger E, Krause E, Oksche A, Rosenthal W, Schulein R. Disease-causing V vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic 004; 5: Robben JH, Sze M, Knoers NVAM, Deen MT. Rescue of vasopressin V receptor mutants by chemical chaperones: specificity and mechanism. Mol Biol Cell 006; 17: Oueslati M, Hermosilla R, Schonenberger E, Oorschot V, Beyermann M, Wiesner B, Schmidt A, Klumperman J, Rosenthal W, Schulein R. Rescue of a nephrogenic diabetes insipidus-causing vaospressin V receptor mutant by cell-penetrating peptides. J Biol Chem 007; 8: Tan CM, Nickols HH, Limbird LE. Appropriate polarization following pharmacological rescue of V vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J Biol Chem 003; 78: Bernier V, Lagace M, Lonergan M, Arthus MF, Bichet DG, Bouvier M. Functional rescue of the constitutively internalized V vasopressin receptor mutant R137H by the pharmacological chaperone action of SR Mol Endocrinol 004; 18: Robben JH, Sze M, Knoers N, Deen MT. Functional rescue of vasopressin V receptor mutants in mdck cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J hysiol Renal hysiol 007; 9: F53 F60. 6 Schrier RW, Gross, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; the SALT Investigators. Tolvaptan, a selective oral vasopressin V-receptor antagonist, for hyponatremia. N Engl J Med 006; 355: Farmakis D, Filippatos G, Kremastinos D, Gheorghiade M. Vasopressin and vasopressin antagonists in heart failure and hyponatremia. Curr Heart Fail Rep 008; 5: Robben JH, Kortenoeven MLA, Sze M, Yae C, Milligan G, Oorschot V, Klumperman J, Knoers NVAM, Deen MT. Intracellular activation of vasopressin V receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. roc Natl Acad Sci USA 009; 106: Jean-Alphonse F, erkovska S, Frantz MC, Durroux T, Mejean C, Morin D, Loison S, Bonnet D, Hibert M, Mouillac B, Mendre C. Biased agonist pharmacochaperones of the AV V receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 009; 0: Noorwez SM, Malhotra R, McDowell JH, Smith KA, Krebs M, Kaushal S. Retinoids assist the cellular folding of the autosomal dominant retinitis pigmentosa opsin mutant 3H. J Biol Chem 004; 79: Rus R, Haag C, Bumke-Vogt C, Bahr V, Mayr B, Mohlig M, Schulze E, Frank-Raue K, Raue F, Schofl C. Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic NS R-568 improves signal transduction of mutant receptors. J Clin Endocrinol Metab 008; 93: Conn M, Ulloa-Aguirre A, Ito J, Janovick JA. G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. harmacol Rev 007; 59: Janovick JA, Goulet M, Bush E, Greer J, Wettlaufer DG, Conn M. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropinreleasing hormone receptor. J harmacol Exp Ther 003; 305: Dupre DJ, Baragli A, Rebois RV, Ethier N, Hebert TE. Signalling complexes associated with adenylyl cyclase II are assembled during their biosynthesis. Cell Signal 007; 19: Dupre DJ, Robitaille M, Ethier N, Villeneuve LR, Mamarbachi AM, Hebert TE. Seven transmembrane receptor core signaling complexes are assembled prior to plasma membrane trafficking. J Biol Chem 006; 81: Revankar CM, Cimino DF, Sklar LA, Arterburn JB, rossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 005; 307: ª 010 The Authors. Journal Compilation ª 010 Blackwell ublishing Ltd, Journal of Neuroendocrinology,,