E L Los

Publication Details
Article Title: Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus.

First Author: E L Los

All Authors: Los EL, Deen PM, Robben JH

Journal Title: Journal of neuroendocrinology

Abstract: 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 (AVP), which binds to its type 2 receptor (V2R) in the kidney. Mutations in the gene encoding the V2R 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 AVP. Many of these mutations are missense mutations that do not interfere with the intrinsic functionality of V2R, but cause its retention in the endoplasmic reticulum (ER), making it unavailable for AVP 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 V2R mutants, leading to increased cAMP levels and translocation of aquaporin-2 to the apical membrane. This makes V2R-specific cell-permeable agonists very promising therapeutics for NDI as a result of misfolded V2R receptors.

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Authors: Downes K, Marcovecchio ML, Clarke P, Cooper JD, Ferreira RC, Howson JM, Jolley J, Nutland S, Stevens HE, Walker NM, Wallace C, Dunger DB, Todd JA

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Authors: Kullberg CE, Abrahamsson M, Arnqvist HJ, Finnström K, Ludvigsson J,

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