{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T23:09:16Z","timestamp":1765667356495,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011019","name":"Nemzeti Kutat\u00e1si Fejleszt\u00e9si \u00e9s Innov\u00e1ci\u00f3s Hivatal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011019","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The urine concentrating function of the kidney is essential to maintain the water homeostasis of the human body. It is mainly regulated by the arginine-vasopressin (AVP), which targets the type 2 vasopressin receptor (V2R) in the kidney. The inability of V2R to respond to AVP stimulation leads to decreased urine concentration and congenital nephrogenic diabetes insipidus (NDI). NDI is characterized by polyuria, polydipsia, and hyposthenuria. In this study, we identified a point mutation (S127F) in the <jats:italic>AVPR2<\/jats:italic> gene of an NDI patient, and we characterized the impaired function of the V2R mutant in HEK293 cells. Based on our data, the S127F-V2R mutant is almost exclusively located intracellularly in the endoplasmic reticulum (ER), and very few receptors were detected at the cell surface, where the receptor can bind to AVP. The overexpressed S127F-V2R mutant receptor has negligible cAMP generation capability compared to the wild-type receptor in response to AVP stimulation. Since certain misfolded mutant proteins, that are retained in the ER, can be rescued by pharmacological chaperones, we examined the potential rescue effects of two pharmacochaperones on the S127F-V2R. We found that pretreatment with both tolvaptan (an established V2R inverse agonist) and MCF14 compound (a cell-permeable high-affinity agonist for the V2R) were capable of partially restoring the cAMP generating function of the receptor in response to vasopressin stimulation. According to our data, both cell permeant agonists and antagonists can function as pharmacochaperones, and serve as the starting compounds to develop medicines for patients carrying the S127F mutation.<\/jats:p>","DOI":"10.3389\/fphar.2022.811836","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T08:13:30Z","timestamp":1643098410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Functional Rescue of a Nephrogenic Diabetes Insipidus Causing Mutation in the V2 Vasopressin Receptor by Specific Antagonist and Agonist Pharmacochaperones"],"prefix":"10.3389","volume":"13","author":[{"given":"Laura","family":"Szalai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e1s","family":"Szir\u00e1ki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3 S\u00e1ndor","family":"Erd\u00e9lyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinga Bernadett","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikl\u00f3s","family":"T\u00f3th","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e1s D\u00e1vid","family":"T\u00f3th","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e1bor","family":"Turu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Bonnet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard","family":"Mouillac","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"Hunyady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e1s","family":"Balla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1681\/ASN.V1161044","article-title":"Report of 33 Novel AVPR2 Mutations and Analysis of 117 Families with X-Linked Nephrogenic Diabetes Insipidus","volume":"11","author":"Arthus","year":"2000","journal-title":"J. Am. Soc. Nephrol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/978-3-030-25905-1_15","article-title":"Nephrogenic Diabetes Insipidus","volume":"111","author":"Balla","year":"2019","journal-title":"Exp. Suppl."},{"key":"B3","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.coph.2004.08.001","article-title":"Pharmacological Chaperone Action on G-Protein-Coupled Receptors","volume":"4","author":"Bernier","year":"","journal-title":"Curr. Opin. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1210\/me.2004-0080","article-title":"Functional rescue of the Constitutively Internalized V2 Vasopressin Receptor Mutant R137H by the Pharmacological Chaperone Action of SR49059","volume":"18","author":"Bernier","year":"","journal-title":"Mol. Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1681\/ASN.2005080854","article-title":"Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus","volume":"17","author":"Bernier","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"B6","first-page":"278","article-title":"Nature and Recurrence of AVPR2 Mutations in X-Linked Nephrogenic Diabetes Insipidus","volume":"55","author":"Bichet","year":"1994","journal-title":"Am. J. Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.beem.2016.02.010","article-title":"Genetic Forms of Nephrogenic Diabetes Insipidus (NDI): Vasopressin Receptor Defect (X-Linked) and Aquaporin Defect (Autosomal Recessive and Dominant)","volume":"30","author":"Bichet","year":"2016","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"B8","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/ki.1989.272","article-title":"Epinephrine and dDAVP Administration in Patients with Congenital Nephrogenic Diabetes Insipidus. Evidence for a Pre-cyclic AMP V2 Receptor Defective Mechanism","volume":"36","author":"Bichet","year":"1989","journal-title":"Kidney Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/357333a0","article-title":"Molecular Cloning of the Receptor for Human Antidiuretic Hormone","volume":"357","author":"Birnbaumer","year":"1992","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1007\/s00424-008-0498-1","article-title":"Physiology and Pathophysiology of the Vasopressin-Regulated Renal Water Reabsorption","volume":"456","author":"Boone","year":"2008","journal-title":"Pflugers Arch."},{"key":"B11","doi-asserted-by":"publisher","first-page":"eabg5628","DOI":"10.1126\/sciadv.abg5628","article-title":"Cryo-electron Microscopy Structure of the Antidiuretic Hormone Arginine-Vasopressin V2 Receptor Signaling Complex","volume":"7","author":"Bous","year":"2021","journal-title":"Sci. Adv."},{"key":"B12","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1097\/00005344-199202000-00011","article-title":"Spare Receptors for Beta-Adrenoceptor-Mediated Positive Inotropic Effects of Catecholamines in the Human Heart","volume":"19","author":"Brown","year":"1992","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"605","DOI":"10.3389\/fphar.2019.00605","article-title":"A Receptor Model with Binding Affinity, Activation Efficacy, and Signal Amplification Parameters for Complex Fractional Response versus Occupancy Data","volume":"10","author":"Buchwald","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1097\/01.gim.0000223554.46981.7a","article-title":"Novel Mutations Underlying Nephrogenic Diabetes Insipidus in Arab Families","volume":"8","author":"Carroll","year":"2006","journal-title":"Genet. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/nature02265","article-title":"Therapeutic Approaches to Protein-Misfolding Diseases","volume":"426","author":"Cohen","year":"2003","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1210\/me.2013-1424","article-title":"Altered Agonist Sensitivity of a Mutant V2 Receptor Suggests a Novel Therapeutic Strategy for Nephrogenic Diabetes Insipidus","volume":"28","author":"Erd\u00e9lyi","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1038\/ki.2015.181","article-title":"Mutation in the V2 Vasopressin Receptor Gene, AVPR2, Causes Nephrogenic Syndrome of Inappropriate Diuresis","volume":"88","author":"Erd\u00e9lyi","year":"2015","journal-title":"Kidney Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1056\/NEJMoa042743","article-title":"Nephrogenic Syndrome of Inappropriate Antidiuresis","volume":"352","author":"Feldman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1038\/nm935","article-title":"Inhibition of Renal Cystic Disease Development and Progression by a Vasopressin V2 Receptor Antagonist","volume":"9","author":"Gattone","year":"2003","journal-title":"Nat. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"14B","DOI":"10.1016\/j.amjcard.2005.03.004","article-title":"Current Treatments and Novel Pharmacologic Treatments for Hyponatremia in Congestive Heart Failure","volume":"95","author":"Goldsmith","year":"2005","journal-title":"Am. J. Cardiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.1681\/ASN.2008121289","article-title":"Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus","volume":"20","author":"Jean-Alphonse","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"F931","DOI":"10.1152\/ajprenal.00604.2013","article-title":"The Physiological and Pathophysiological Functions of Renal and Extrarenal Vasopressin V2 Receptors","volume":"306","author":"Juul","year":"2014","journal-title":"Am. J. Physiol. Ren. Physiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/s41467-018-02868-y","article-title":"High Capacity in G Protein-Coupled Receptor Signaling","volume":"9","author":"Keshelava","year":"2018","journal-title":"Nat. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"22460","DOI":"10.1074\/jbc.M116.733220","article-title":"Analysis of the V2 Vasopressin Receptor (V2R) Mutations Causing Partial Nephrogenic Diabetes Insipidus Highlights a Sustainable Signaling by a Non-peptide V2R Agonist","volume":"291","author":"Makita","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1210\/er.2012-1044","article-title":"Nephrogenic Diabetes Insipidus: Essential Insights into the Molecular Background and Potential Therapies for Treatment","volume":"34","author":"Moeller","year":"2013","journal-title":"Endocr. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1172\/JCI8688","article-title":"Pharmacological Chaperones rescue Cell-Surface Expression and Function of Misfolded V2 Vasopressin Receptor Mutants","volume":"105","author":"Morello","year":"2000","journal-title":"J. Clin. Invest."},{"key":"B27","doi-asserted-by":"publisher","first-page":"11663","DOI":"10.1073\/pnas.90.24.11663","article-title":"Cellular and Subcellular Immunolocalization of Vasopressin-Regulated Water Channel in Rat Kidney","volume":"90","author":"Nielsen","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3434","DOI":"10.1210\/jcem.82.10.4312","article-title":"Detection of Skewed X-Inactivation in Two Female Carriers of Vasopressin Type 2 Receptor Gene Mutation","volume":"82","author":"Nomura","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"F257","DOI":"10.1152\/ajprenal.00491.2005","article-title":"Cell Biological Aspects of the Vasopressin Type-2 Receptor and Aquaporin 2 Water Channel in Nephrogenic Diabetes Insipidus","volume":"291","author":"Robben","year":"2006","journal-title":"Am. J. Physiol. Ren. Physiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"F253","DOI":"10.1152\/ajprenal.00247.2006","article-title":"Functional rescue of Vasopressin V2 Receptor Mutants in MDCK Cells by Pharmacochaperones: Relevance to Therapy of Nephrogenic Diabetes Insipidus","volume":"292","author":"Robben","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/s0889-8529(05)70207-3","article-title":"Antidiuretic Hormone. Normal and Disordered Function","volume":"30","author":"Robertson","year":"2001","journal-title":"Endocrinol. Metab. Clin. North. Am."},{"key":"B32","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1111\/j.1600-0854.2004.00231.x","article-title":"A Cure for Traffic Jams: Small Molecule Chaperones in the Endoplasmic Reticulum","volume":"5","author":"R\u00f6misch","year":"2004","journal-title":"Traffic"},{"key":"B33","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/359233a0","article-title":"Molecular Identification of the Gene Responsible for Congenital Nephrogenic Diabetes Insipidus","volume":"359","author":"Rosenthal","year":"1992","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1056\/NEJMoa065181","article-title":"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia","volume":"355","author":"Schrier","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/0167-0115(93)90184-a","article-title":"The Vasopressin Type 2 Receptor Gene. Chromosomal Localization and its Role in Nephrogenic Diabetes Insipidus","volume":"45","author":"Seibold","year":"1993","journal-title":"Regul. Pept."},{"key":"B37","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/psc.714","article-title":"Analysis of Interactions Responsible for Vasopressin Binding to Human Neurohypophyseal Hormone Receptors-Molecular Dynamics Study of the Activated Receptor-Vasopressin-G(alpha) Systems","volume":"12","author":"Slusarz","year":"","journal-title":"J. Pept. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1021\/jm051075m","article-title":"Molecular Docking-Based Study of Vasopressin Analogues Modified at Positions 2 and 3 with N-Methylphenylalanine: Influence on Receptor-Bound Conformations and Interactions with Vasopressin and Oxytocin Receptors","volume":"49","author":"Slusarz","year":"","journal-title":"J. Med. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1038\/ki.2008.111","article-title":"A Mouse Model for Polycystic Kidney Disease through a Somatic In-Frame Deletion in the 5' End of Pkd1","volume":"73","author":"Starremans","year":"2008","journal-title":"Kidney Int."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1074\/jbc.M111.268797","article-title":"V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists","volume":"287","author":"Takahashi","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"35678","DOI":"10.1074\/jbc.M301888200","article-title":"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","volume":"278","author":"Tan","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1056\/NEJMoa1205511","article-title":"Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease","volume":"367","author":"Torres","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1111\/j.1600-0854.2004.00232.x","article-title":"Pharmacologic rescue of Conformationally-Defective Proteins: Implications for the Treatment of Human Disease","volume":"5","author":"Ulloa-Aguirre","year":"2004","journal-title":"Traffic"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1681\/ASN.V1091958","article-title":"Clinical Presentation and Follow-Up of 30 Patients with Congenital Nephrogenic Diabetes Insipidus","volume":"10","author":"Van Lieburg","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1007\/s00467-012-2118-8","article-title":"Congenital Nephrogenic Diabetes Insipidus: the Current State of Affairs","volume":"27","author":"Wesche","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"47254","DOI":"10.1074\/jbc.M408154200","article-title":"Pharmacochaperones post-translationally Enhance Cell Surface Expression by Increasing Conformational Stability of Wild-type and Mutant Vasopressin V2 Receptors","volume":"279","author":"W\u00fcller","year":"2004","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.811836\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T15:22:51Z","timestamp":1643296971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.811836\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,25]]},"references-count":46,"alternative-id":["10.3389\/fphar.2022.811836"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.811836","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2022,1,25]]},"article-number":"811836"}}