Department of Physiology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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 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 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 Loffing and colleagues (10) speculate that serous cells in the airway
have high basal rates of Cl
ARTICLE
Top
Article
References
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).
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.
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.
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.
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ACKNOWLEDGEMENTS |
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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.
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REFERENCES |
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