Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells
| Title: | Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells |
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| Authors: | Stefan, Eduard; Wiesner, Burkhard; Baillie, George S.; Mollajew, Rustam; Henn, Volker; Lorenz, Dorothea; Furkert, Jens; Santamaria, Katja; Nedvetsky, Pavel; Hundsrucker, Christian; Beyermann, Michael; Krause, Eberhard; Pohl, Peter; Gall, Irene; MacIntyre, Andrew N.; Bachmann, Sebastian; Houslay, Miles D.; Rosenthal, Walter; Klussmann, Enno |
| Publisher: | American Society of Nephrology |
| Date Published: | January 01, 2007 |
| Reference Number: | 716 |
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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)
When researchers use the term compartmentalization in a biological context, it refers to the method tiny cell compartments called organelles use to isolate different cellular structures from other organelles. For example, some intracellular structures are isolated within the cell by being encircled by membranes. Inside these membrane-bound compartments, multiple intracellular pH and different enzyme systems are isolated from other cellular structures. This enables the cell to carry out different metabolic activities at the same time. This ability for cellular structures to compartmentalize is vital for cell function. The research by Stefan, et al., explores how compartmentalization of cAMP/PKA signaling by PDE4 helps regulate AQP2, in particular, the movement of AQP2 from the cell interior to the cell membrane.
There is a specific chemical sequence that occurs within the principal cells of the kidney collecting duct that allows the kidney to reabsorb water and therefore concentrate urine. The hormone, arginine vasopressin (AVP), binds with the vasopressin 2 receptor (V2R) on the outer membrane of the principal cell. This stimulates adenylyl cyclase within the cell, and this elevates cellular levels of cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA). PKA then adds a phosphate group to (i.e., phosphorylates) aquaporin-2 (AQP2).
AQP2 is a protein that acts as a channel through which water can enter the cell when AQP2 is inserted into the cell membrane. However, AQP2 resides in the cell interior within tiny sacs called vesicles. It is only when AQP2 is phosphorylated that it begins to travel from the cell interior to the cell membrane, where it can act as a water channel. The cAMP/PKA signaling systems that are responsible for AQP2’s movement to the cell membrane are compartmentalized by A kinase anchoring proteins (AKAP). AKAPs keep PKA attached to the vesicles in the cell interior which contain AQP2.
Phosphodiesterases (PDE) help regulate PKA activity by breaking down cAMP, thus terminating PKA signaling. When PKA signaling is terminated, AQP2 is no longer stimulated to translocate to the cell membrane. PDE4D (a type of PDE4 specific to cAMP) and PKA are both tethered to the outside of the vesicles that contain AQP2. When the researchers added rolipram, a drug known to inhibit PDE4, to their laboratory cell cultures, they found increases in AKAP-tethered PKA activity on the vesicles containing AQP2. This increased the movement of AQP2 to the cell membrane, resulting in water passing into the cell.
Stefan, et al., determined that AKAP18 delta, a member of the family of AKAPs, is located on the outside of AQP2 bearing vesicles. It interacts with PDE4D and PKA. When AVP binds with V2R and initiates the chemical sequence that signals AQP2 exocytosis, PDE4D also travels to the cell membrane because it is anchored to the vesicles that AQP2 travel in. At the cell membrane, PDE4D is activated by PKA phosphorylation. PDE4D, in turn, reduces PKA signaling, which affects the redistribution of AQP2 to the plasma membrane and reduces the cell’s ability to let water pass through its membrane. Taken together, the research team’s data signifies that the interaction among PDE4D, AKAP18 delta and PKA, all anchored to AQP2-bearing vesicles, comprises a compartmentalized and physiologically relevant signal transduction module that involves an ordered sequence of biochemical reactions that affects AQP2 movement to and from the cell membrane. The process described by the researchers affects the cell’s ability to absorb water. This finding may prove relevant to NDI research as inhibiting PDE4 increases the AVP-induced rise in cAMP, and this promotes AQP2’s insertion into the plasma membrane. The researchers suggest that some combination of PDE4 inhibitors combined with a cAMP-elevating agent may serve as a treatment modality for people with the X-linked type of NDI.