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Renal Unit and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129
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ABSTRACT |
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Aquaporins (AQPs) are a family of functionally important water channel proteins that are of special cell biological interest because of their diverse intracellular targeting and trafficking properties. AQPs have been found in many different cells and tissues. This short review summarizes recent work that addresses the regulation of AQP2 trafficking in response to vasopressin.
vasopressin; phosphorylation
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ARTICLE |
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THE AQUAPORINS (AQPs) are a family of transmembrane channel proteins that are present in diverse epithelial cell membranes and serve to regulate transepithelial water reabsorption and body fluid homeostasis. Aquaporins have been found in many different cells and tissues (1, 6, 13, 22), but this brief review will concentrate on their distribution and regulation in renal epithelial cells. AQP1, the first aquaporin to be characterized (2), is present in both apical and basolateral plasma membranes of proximal tubules and thin descending limbs of Henle (31, 33). These tubule segments have a high constitutive permeability to water. AQP2 is the vasopressin-regulated water channel that in the kidney is expressed exclusively in collecting duct principal cells (1, 13), although our recent studies have also located this protein in the testis and epithelial cells lining the vas deferens (28). The intracellular location of AQP2 shifts from intracellular vesicles to the apical plasma membrane upon vasopressin stimulation (29, 32, 39), as indicated in Fig. 1. Several mutations in the AQP2 protein result in autosomal nephrogenic diabetes insipidus (8, 9, 27), confirming the importance of this protein in urinary concentration. In contrast, AQP3 and AQP4 are located on the basolateral plasma membrane of principal cells, and this membrane localization is not acutely regulated by vasopressin (12, 17, 36). The list of cloned aquaporins is steadily growing, and the most recent addition to the group at the time of this writing is AQP8, which is expressed in developing spermatozoa in the testis (16).
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AQP1, AQP3, and AQP4 are located on plasma membranes constitutively, whereas AQP2 is the only aquaporin that has been shown to follow a regulated pathway leading to plasma membrane expression. The aquaporins, therefore, are a family of functionally important proteins that are also of special cell biological interest because of their diverse intracellular targeting and trafficking properties. The signals responsible for this differential intracellular handling of the aquaporins are unknown, but some signaling domains are beginning to be identified.
Vasopressin-induced translocation of AQP2. In the kidney, AQP2 is found only in collecting duct principal cells. Several studies have shown that AQP2 is moved from intracellular vesicles to the plasma membrane upon vasopressin stimulation (Fig. 1), confirming the shuttle hypothesis of vasopressin action that was proposed almost two decades ago (38). The mechanisms underlying this hormonally induced regulated trafficking of AQP2 are the subject of intense current investigation, using a variety of systems including transfected epithelial cells that express AQP2. The first example of vasopressin-induced translocation of AQP2 in a heterologous expression system was provided by Katsura et al. (19, 21), and subsequent studies have also described cAMP-dependent translocation of AQP2 in transformed collecting duct epithelial cells (37) and in MDCK cells (10). In the original study, LLC-PK1 epithelial cells were used, and the AQP2 was inserted into the basolateral plasma membrane. In the two other cell types so far examined, apical insertion, more closely resembling the polarity of insertion in principal cells in vivo, was reported. The reason for the basolateral targeting of AQP2 in LLC-PK1 cells is unclear, but previous studies using other transfected chimeric proteins have also shown that targeting to opposite poles of the cell occurs in LLC-PK1 and MDCK cells (15). Thus regulated trafficking of AQP2 occurs in a variety of transfected cell lines, and it may be possible to use these unique targeting properties to examine how polarity signals on proteins are interpreted by different cell types, as well as how they are translated by the intracellular transport machinery.
Role of protein kinase A phosphorylation in AQP2 trafficking. Following vasopressin binding to its receptor, intracellular cAMP levels increase via G protein activation of adenylyl cyclase in principal cells (Fig. 1). The subsequent activation of protein kinase A (PKA) leads to phosphorylation of AQP2 on a serine residue at position 256 on the cytoplasmic COOH terminal. This phosphorylation event is required to increase the water permeability of oocytes expressing AQP2 (23). However, other studies showed that the water permeability of isolated kidney papillary vesicles containing AQP2 was not modified by the phosphorylation state of AQP2 (24). Phosphorylation could in theory modulate the water permeability of AQP2 in the plasma membrane, or it could be involved in the regulated trafficking of vesicles containing AQP2 to the plasma membrane. To examine this issue, LLC-PK1 cells were transfected with an AQP2 construct bearing a point mutation that converted the serine-256 residue to an alanine (S256A AQP2). This construct was located primarily on perinuclear intracellular vesicles in the basal state, and it did not translocate to the cell surface after stimulation of the cells with either vasopressin or forskolin (20). A similar result was independently obtained, also in LLC-PK1 cells, by means of a cell surface biotinylation assay to monitor the regulated cell surface expression of wild-type and S256A AQP2 (14). Thus these results indicate that PKA-mediated phosphorylation of the serine-256 residue on AQP2 is essential for the regulated movement of AQP2-containing vesicles to the plasma membrane upon elevation of intracellular cAMP, as illustrated in Fig. 1.
The cytoskeleton and vesicle trafficking. The mechanism by which phosphorylation induces vesicle trafficking is unknown, but this presumably involves interaction of AQP2-containing vesicles with the cytoskeleton. Drugs that disrupt microtubules or actin microfilaments have long been known to inhibit the hormonally induced permeability response in target epithelia (35), and more recently it was shown that microtubules are required for the apical polarization of AQP2 in principal cells (32). We have recently shown that AQP2 is an actin-binding protein (5), and the microtubule motor dynein is also involved in the permeability response to vasopressin (3). Thus, an interactive process involving vesicle movement along microtubules, associated with actin-mediated events, is probably required for vesicle transport. One scenario shown in Fig. 1 is that microtubule-based movement brings vesicles close to the membrane, and then a modification in the actin cell web is required to allow vesicle access to the plasma membrane. Previous studies have indeed shown that a rearrangement of the subapical actin network occurs in toad bladder and collecting duct cells after vasopressin stimulation (11, 34). Whether actin-mediated vesicular transport occurs, or whether the actin network reorganization simply allows the vesicles access to the plasma membrane by removing a physical barrier, remains to be determined. However, studies in other systems have implicated actin and associated proteins such as the myosins, as well as microtubules, in sequential transport steps of vesicle exocytosis (4). Our work on the actin-binding properties of AQP2 coupled with the finding that myosin I is also associated with AQP2-containing vesicles (26) supports the notion that actin, as well as tubulin-based vesicle movement may contribute to vasopressin-induced AQP2 recruitment to the plasma membrane.
Once the vesicles have been brought into close proximity with the plasma membrane, their ultimate exocytotic fusion depends on a host of other membrane-associated and cytosolic proteins that together form a "fusion machine." A description of this complex process, which closely resembles the series of events that are involved in synaptic vesicle fusion, is beyond the scope of this brief article. These concepts were discussed in a recent review from our laboratory (7), and the discovery of similar fusion proteins associated with AQP2-containing vesicles is consistent with other reports showing that the cell biology of the exocytotic fusion process has been conserved in many different cell types (18, 25, 30).| |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38452 and by a fellowship from the National Kidney Foundation to C. E. Gustafson.
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FOOTNOTES |
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1 This report is the third in a series of minireviews, which are based on a symposium on the urinary concentrating mechanism, held at Experimental Biology '97 in New Orleans, LA.
Address for reprint requests: D. Brown, Renal Unit, Massachusetts General Hospital East, 149 13th St., Charlestown, MA 02129.
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