An Extracellular Congenital Nephrogenic Diabetes Insipidus Mutation of the Vasopressin Receptor Reduces Cell Surface Expression, Affinity for Ligand, and Coupling to the Gs/adenylyl Cyclase System
|Title:||An Extracellular Congenital Nephrogenic Diabetes Insipidus Mutation of the Vasopressin Receptor Reduces Cell Surface Expression, Affinity for Ligand, and Coupling to the Gs/adenylyl Cyclase System|
|Authors:||Birnbaumer, Mariel; Gilbert, Stephanie; Rosenthal, Walter|
|Date Published:||July 01, 1994|
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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)
- The enzyme adenylyl cyclase is stimulated, generating the build-up of an important regulator called cAMP.
- The increased levels of cAMP activate protein kinase A, which provide the molecular conditions for water-transporting proteins called aquaporin-2s (AQP2s) to insert themselves in the apex of the cell membranes of the principal cells of the kidney collecting duct.
- The insertion of AQP2s into the principal cells of the kidney collecting duct makes these cells more water permeable so the kidney duct can reabsorb the body water passing through it.
- The liquid not reabsorbed becomes the concentrated urine that is later excreted.
Birnbaumer, et al., studied one V2R gene mutation found in an NDI patient, analyzing its structural alterations and functional characteristics. The mutation expressed itself in the first extracellular loop of the V2R (V2Rs have three extracellular loops. You can look at a diagram of the V2R for a clearer understanding.) The mutation resulted in the amino acid, tryptophan, being in the position the amino acid, arginine, should have occupied.
The effects this structural change had on the mutated V2Rs' functional capabilities were:
- the mutated V2Rs had a 20-fold reduced affinity for AVP,
- they were expressed on the cell surface, the place they must be if they are to bind with AVP, at one-fifth the level of normal V2Rs,
- and their ability to stimulate adenylyl cyclase activity was significantly reduced.
The authors believe this is the first extracellular V2R mutation to be reported in the literature that combines all these functional defects. They conclude this mutation is the molecular basis for their patient's NDI.