Rescue of Vasopressin V2 Receptor Mutants by Chemical Chaperones: Specificity and Mechanism
|Title:||Rescue of Vasopressin V2 Receptor Mutants by Chemical Chaperones: Specificity and Mechanism|
|Authors:||Robben, Joris; Sze, Mozes; Knoers, Nine; Deen, Peter M.T.|
|Publisher:||Molecular Biology of the Cell|
|Date Published:||January 01, 2006|
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Around 50% of the mutations that give rise to NDI are missense mutations. These result in proteins that don’t fully mature and don’t achieve the same shape that they would if they were normal and not mutated. These mutant proteins are held by molecular chaperones in the endoplasmic reticulum (ER), the quality control center of the cell. That is, these mutant proteins are not allowed to travel to that location in the cell membrane where they must go to perform their job. Instead, though they may be capable of performing their function if they could get to the cell membrane, they are retained in the ER. From there, they are escorted out to the proteasomes, which take them apart.
Chemical chaperones are small molecules that stabilize proteins in their native state. In some cases they can help an immature, improperly shaped protein achieve enough of a normal shape to meet the ER quality control requirements so they can exit the ER and travel to their job site. A number of NDI researchers are focusing on chemical chaperones in the hopes that these molecules could be able to rescue missense mutant V2Rs by helping them mature and properly configure so they can exit the ER, bind with AVP and initiate the urine concentration process.
Robben, et al., tested seven chemical chaperones on nine distinct V2R mutant proteins to see if they could rescue the mutants. They also tested the role of decreased temperature and calcium levels in the cell’s ER and in its cytosol (the liquid medium of the cell’s cytoplasm) in rescuing the mutants.
Of the nine mutants, only one, V206D, matured and expressed at the cell membrane in response to the chaperones. V206D was rescued by each of the following chemical chaperones: glycerol, demethyl sufoxide (DMSO), thapsigargin, churcumin and ionomycin. It did not respond to other chaperones or to incubation and growth at 27°C. Performing careful experimentation to better understand the mechanism behind the rescue, the team was able to determine that the rescues did not alter the number of naturally occurring molecular chaperone, calnexin, heat- shock protein (HSP) 70 or HSP90. However, the rescue by thapsigargin, curcumin and ionomycin did involve an elevation of the cytosolic calcium level, not a decrease in the ER calcium level. This was not the case with DMSO, glycerol or SR121463B (SR1), even though these compounds also rescued V206D.
SR1 was also able to bring the mutants it rescued into a more mature and stable development than the chemical chaperones.
Robben, et al.’s , research indicates that use of chemical or pharmacological chaperones must be tailored to specific mutants. That is, there is not one chaperone that can affect a rescue for all missense V2R mutants. However, the scientists believe chemical and pharmacological chaperones still provide a promising approach to treating NDI.