Endocrine Abstracts

Using pharmacological chaperones is one of the most common area to rescue trapped proteins from Endoplasmic reticulum (ER) or Golgi apparatus as therapeutic targets in research of some endocrine disorders. Diabetes insipidus is one of these disorders and AVPR2 is seen mostly mutated in hereditary type of the disorder. As proteins go through a journey from ribosome till the place where they function at, AVPR2 also tracks the same way as a G-protein coupled receptor. A mutation in AVPR2 could effect three dimensional functionally active structure of the protein and it could be trapped in ER or Golgi apparatus. Consequently, its cell surface expression, which primarly locates at the basolateral membrane of principal cells in the collecting duct, could decrease which shows its affects on the syptoms. As a therapeutic agent, SR121463A and SR49059 are commonly used for research the rescue potential of mutant AVPR2s. We aimed to show the rescue potential of SR121463A and SR49059 as a pharmacological chaperones in treated AVPR2 mutants (G12E, R68W, ΔR67_G69/G107W, V88M, R106C, V162A, T273M). These mutants were previously described and functionally analysed by our group. After treatment with SR121463A and SR49059, cell surface expression analyses were done for mutants. This work was funded by The Scientific and Technological Research Council of Turkey (SBAG Project No: 216S304). As a result, these pharmacological chaperones showed that they has a rescue potential at different levels according to the mutation. Some mutations have severe symptoms and also they showed loss of function but we could show the rescue of these some mutants using with SR121463A and SR49059. In conclusion, as a therapeutic target, SR121463A and SR49059 could be used to rescue of some mutated AVPR2s in vitro and many of these kind of targets are mainly used. To get a more clear view, we will perform cAMP accumulations assay and cell imaging analysis for these mutants using with SR121463A and SR49059. In our opinion, these kind of in vitro studies will be helpful to use of these pharmacological chaperones in vivo and shed light to the future studies. Especially for the disorders which have severe symptoms, in vitro and in vivo studies have an importance to reduce the severeness of the symptoms.