EDITORIAL FOCUS
Focus on "Exocytosis is not involved in activation of Clminus secretion via CFTR in Calu-3 airway epithelial cells"

William B. Guggino

Department of Physiology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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RAPID CHANGES IN salt and water movement occur in many epithelial tissues that respond quickly to alterations in overall salt and water balance. For example, the amount of Cl- secreted by the shark rectal gland can vary greatly in response to changes in the external environment (4). To rapidly change the rate of transport, epithelial cells regulate the transport rates of specific ion channels, pumps, and carriers. This regulation commonly occurs by either affecting the activity of an individual transport process and/or the number of transport entities in the plasma membrane. The activity of many ion channels is regulated by voltage, by extracellular ligands, or by intracellular signal transduction mechanisms (6). Thus many ion channels can be easily switched on and off to match the needs of a rapidly changing physiological process. CFTR is an excellent example of a highly regulated Cl- channel (2). The activity of CFTR is controlled by the coordination of two processes, phosphorylation of several sites primarily within the regulatory domain followed by ATP binding and hydrolysis by the nucleotide binding domains. These two processes act together to both switch on and regulate channel opening (3).

In contrast, in some clear-cut cases, once inserted into the plasma membrane the activity of a variety of transporters is difficult to regulate. In those cases, the most effective way to modulate transepithelial transport is to alter the number of transporters in the plasma membrane. For example, it is well known that mature aquaporin water channels move water in an unregulated fashion (1). To modulate overall transepithelial water transport such as in the renal collecting duct, vesicles containing aquaporin 2 water channels are rapidly inserted into the plasma membrane following activation by antidiuretic hormone (8). The specific question addressed by this article in focus is whether exocytosis is involved in the activation of Cl- secretion via CFTR in the human airway serous cell line, Calu-3. Serous cells are located primarily in the submucosal glands of human airway and are known to express CFTR.

The overall question of how much of the function of CFTR is dependent on its insertion into the plasma membrane can be answered by the phrase "it depends." CFTR is expressed in a variety of tissues, including airway, pancreas, gastrointestinal tract, heart, and kidney, where it participates in ion transport (5). Thus how much of CFTR-mediated transport is controlled by exocytosis may depend critically on which organ is being considered. Moreover, when cultured cells are being studied, it may also depend on the degree of differentiation of the cells.

For example, in the current article in focus (Ref. 10; see p. C913 in this issue), Loffing and colleagues demonstrate that exocytosis of CFTR-containing vesicles is not involved in the activation of Cl- secretion in Calu-3 cells. Similarly, exocytic delivery of CFTR does not occur in gallbladder epithelium (14). Presumably in these tissues, activation of resident CFTR is sufficient to regulate transport. In other tissues such as the shark rectal gland, bronchial epithelial cells, and in transporting cell lines such as Madin-Darby canine kidney (MDCK) II and A6, cAMP increases the amount of CFTR in the apical cell membrane (7, 9, 11, 13). In T84 cells (a colonic epithelial cell line), the results are conflicting, suggesting either that culture conditions may affect the machinery for cAMP-dependent exocytosis of CFTR (12, 15) or that methodological difficulties in localizing CFTR in the plasma membrane make it difficult to detect exocytosis of CFTR. Thus the question of how much of a role exocytosis plays in regulating the transport of CFTR in T84 cells is still unresolved.

Loffing and colleagues (10) speculate that serous cells in the airway have high basal rates of Cl- and antibiotic secretion. This may require that high levels of CFTR be present at all times to support such a high level of transport. Given that CFTR is highly regulated both by phosphorylation and ATP binding and hydrolysis, then why do some tissues need to control its function further by rapidly moving CFTR to the plasma membrane via exocytosis? One may speculate that stimulation of transport via CFTR, by increasing the number of channels though exocytosis, may occur only in tissues such as the shark rectal gland, where very large and rapid changes in transport occur.

    ACKNOWLEDGEMENTS

This report was funded by grants from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Cystic Fibrosis Foundation.

    REFERENCES
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Am J Physiol Cell Physiol 275(4):C911-C912
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