From Vasopressin Receptor to Water Channel: Intracellular Traffic, Constraint and By-pass
| Title: | From Vasopressin Receptor to Water Channel: Intracellular Traffic, Constraint and By-pass |
|---|---|
| Authors: | Laycock, John F.; Hanoune, J. |
| Publisher: | Journal of Endocrinology |
| Date Published: | December 01, 1998 |
| Reference Number: | 439 |
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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 next step in the sequence is not entirely clear, but it involves the introduction of a phosphate group (a process called phosphorylation) to protein kinase A (PKA). This precedes the final step in the molecular process: the translocation of aquaporin-2s (AQP2s) from within the principal cell to the apical membrane of the cell.
The AQP2s are proteins that act as channels through which water can flow. They are located within sacs called aggrephores. The aggrephores, in response to the presence of VP, travel from within the cell to the apical membrane. Once they reach it, they fuse with it, and the AQP2s are inserted into the membrane. This allows much more water than usual to travel across the cell membrane. And this is what allows the kidneys to reabsorb the water flowing through the distal nephrons. When VP is absent from the vicinity of the principal cell, the AQP2s are retrieved from the apical membrane which returns to its normal state, which permits very little water to cross it.
VP regulates AQP2. In the presence of VP there is an immediate increase in the presence of AQP2 in the apical membranes and an increased movement of aggrephores towards the apical membranes. VP also causes a long-term increase in AQP2 synthesis within the principal cells. VP, then, regulates both the translocation and the production (expression) of AQP2. But the V2R-to-AQP2 pathway (sequence) is filled with molecules and the interaction of molecules that can additionally regulate this sequence. This is the subject matter Laycock and Hanoune review in their article.
Generally, the effects of hormones can be in part regulated by a change in receptor number and/or affinity. For example, when the amount of a specific hormone circulating throughout the system is greater than its normal range, the number of receptors specific to that hormone will reduce. And when the amount of a specific hormone is less than the normal range, then the number of its receptors will expand. V2Rs do not completely conform to this generality. When there is a greater than normal circulating concentration of VP, the number of V2Rs will decline. However, when the circulating concentration of VP is lower than normal, the number of V2Rs is reduced.
Thus, when VP is absent, there is a decrease in V2Rs. This suggests to researchers that circulating VP influences the synthesis of V2Rs in the collecting duct cells through a mechanism mediated by the V2Rs themselves.
The absence of VP also causes a decrease in the number of inhibitory G proteins (Gi). This is probably because V2Rs are coupled to both Gi and Gs proteins. VP appears to be necessary for the maintenance of a certain level of AC expression. In the absence of VP, there is a reduction of expression of three forms of AC (AC5, AC6 and AC9). In the presence of VP, the expression of these forms of AC increases.
Researchers have discovered that the AQP2 gene has a segment which responds to cAMP. The presence of cAMP helps stimulate AQP2 synthesis in the principal cell of the kidney collecting duct. Since there is an increase in cAMP in response to the VP/V2R bond, it may be said that VP influences the expression of AQP2. As mentioned, VP influences the translocation of AQP2 as well as its synthesis. However, there is research to suggest that the molecular sequence required for translocation might be different for that required for increased expression.
When there is a higher circulating concentration of VP than normal, it causes a reduction in the number of V2Rs, but an increase in the numbers of AQP2s. Researchers think this may be a way the body adapts to dehydration. Dehydration causes an increase in circulating levels of VP, which leads to a reduction of V2Rs. A reduction of V2Rs would be expected to lead to a reduction of AQP2s, which would lead to a reduction in the amount of body water the kidney could reabsorb from the collecting ducts. But under conditions of dehydration the body needs to conserve as much water as possible, and the body does this by increasing the number of AQP2s. That the body can have a reduction of V2Rs simultaneously with an increase in AQP2s suggests there might be two different VP-to-AQP2 pathways (molecular sequences). The second pathway may, like the first, be stimulated by VP, but unlike the first pathway, it may be independent of AC. This second pathway may only become available when the circulating concentration of VP is above normal.