Rescue of Vasopressin V2 Receptor Mutants by Chemical Chaperones: Specificity and Mechanism
| Autor: | Peter Mt Deen, Joris H. Robben, Nine V A M Knoers, M. Sze |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Receptors
Vasopressin Health aging / healthy living [IGMD 5] Cell Membrane Permeability Curcumin Thapsigargin Membrane transport and intracellular motility [NCMLS 5] Biology Endoplasmic Reticulum Ligands Sensitivity and Specificity Calcium in biology Cell Line chemistry.chemical_compound Cytosol Dogs Calnexin Arginine vasopressin receptor 2 Animals Humans Molecular Biology Renal disorder [IGMD 9] Ionomycin Endoplasmic reticulum Cell Membrane Biological Transport Valine Articles Cell Biology Hsp90 Renal disorders [UMCN 5.4] chemistry Biochemistry Mutation biology.protein Calcium Chemical chaperone Molecular Chaperones |
| Zdroj: | Molecular Biology of the Cell, 17, 379-86 Molecular Biology of the Cell, 17, 1, pp. 379-86 |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | Contains fulltext : 50366.pdf (Publisher’s version ) (Open Access) Because missense mutations in genetic diseases of membrane proteins often result in endoplasmic reticulum (ER) retention of functional proteins, drug-induced rescue of their cell surface expression and understanding the underlying mechanism are of clinical value. To study this, we tested chemical chaperones and sarco(endo)plasmic reticulum Ca2+ ATPase pump inhibitors on Madin-Darby canine kidney cells expressing nine ER-retained vasopressin type-2 receptor (V2R) mutants involved in nephrogenic diabetes insipidus. Of these nine, only V2R-V206D showed improved maturation and plasma membrane rescue with glycerol, dimethyl sulfoxide (DMSO), thapsigargin/curcumin, and ionomycin but not with other osmolytes or growth at 27 degrees C. This revealed that rescue is mutant specific and that this mutant is prone to rescue by multiple compounds. Rescue did not involve changed expression of molecular chaperones calnexin, heat-shock protein (HSP) 70, or HSP90. V2R antagonist SR121463B treatment revealed that V2R-V206D and V2R-S167T were rescued and matured to a greater extent, suggesting that the rescuing activity of a pharmacological versus chemical chaperone is broader and stronger. Calcium measurements showed that rescue of V2R-V206D by thapsigargin, curcumin, and ionomycin was because of increased cytosolic calcium level, rather than decreased endoplasmic reticulum calcium level. The molecular mechanism underlying rescue by DMSO, glycerol, and SR121463B is different, because with these compounds intracellular calcium levels were unaffected. |
| Databáze: | OpenAIRE |
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