School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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ABSTRACT |
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Regulated secretion in
exocrine and neuroendocrine cells occurs through exocytosis of
secretory granules and the subsequent release of stored small molecules
and proteins. The introduction of biophysical techniques with high
temporal and spatial resolution, and the identification of
Ca2+-dependent and -independent "docking" and
"fusion" proteins, has greatly enhanced our understanding of
exocytosis. The cloning of families of ion channel proteins, including
intracellular ion channels, has also revived interest in the role of
secretory granule ion channels in exocytotic secretion. Thus secretory
granules of pancreatic acinar cell express a ClC-2 Cl
channel, a HCO
-cells, a granular ClC-3 Cl
channel
provides a shunt pathway for a vacuolar-type H+-ATPase.
Acidification "primes" the granules for Ca2+-dependent
exocytosis and release of insulin. In summary, secretory granules are
equipped with specific sets of ion channels, which modulate regulated
exocytosis and the release of macromolecules. These channels could
represent excellent targets for therapeutic interventions to control
exocytotic secretion in relevant diseases, such as pancreatitis, cystic
fibrosis, or diabetes mellitus.
acini; -cells; secretion; zymogen granules; sulfonylureas
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INTRODUCTION |
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EXOCRINE AND ENDOCRINE CELLS,
such as pancreatic acinar or -cells, are morphologically
characterized by the presence of intracellular membrane-bound vesicles
or granules that secrete their content into the extracellular milieu in
a regulated manner. A key aspect of regulated secretion concerns
exocytosis and release of macromolecular secretory products, for
instance, digestive proenzymes (the "zymogens") in pancreatic
acinar cells or insulin in pancreatic
-cells. In this process,
secretory granules gather beneath the cell membranes in clusters and
lie there waiting until a signal reaching the cell membrane induces the
granules to fuse with the plasma membrane (PM) and to discharge their
stored macromolecules and/or solute molecules into the cell exterior.
The sequence of events preceding and accompanying granule export has
been described in great detail by ultrastructural techniques
(143). A decisive element of this process is a
"fusion-fission" reaction between the membrane of secretory
granules and the PM of secretory cells, which may also involve the
formation of proteinaceous pores between apposed membranes as the basis
for fusion (128).
Up to about 1990, the term "exocytosis" described the export process of membrane-impermeant molecules stored within the secretory granules (6). Exocytosis was viewed as comprising several distinct stages, whose nomenclature had been established on the basis of ultrastructural studies (143). After granule assembly in the Golgi and "translocation" beneath the PM, a stimulus would lead to the "fusion" or juxtaposition of granules and PM, a process that would require an intracellular signal, such as an increase of intracellular Ca2+ concentration ([Ca2+]). This initial fusion occurred between the PM inner leaflet and granule outer leaflet (the "pentalaminar complex"). Finally, the barrier between granule interior and extracellular medium would break (undergoing "fission") and secretion would ensue.
The ultrastructural studies by Palade (143) led Pollard
and coworkers (151) to propose a "chemiosmotic
hypothesis of exocytosis," according to which H+ and
Cl fluxes through granule channels and transporters were
energetically coupled to granule fusion and fission via osmotic
swelling of the secretory granules. This model was based on experiments
in cell groups and isolated granules. Subsequent studies on isolated cells using techniques with a higher temporal and spatial resolution seem to have disproved the hypothesis forwarded by Pollard (see Refs.
40, 234).
The introduction of electrophysiological and optical methods with high temporal and spatial resolution, the identification of Ca2+-dependent and -independent proteins participating in the fusion-fission reaction, and the application of kinetic analysis to the process of granular secretion have contributed to a better understanding of regulated vesicular secretion. This allowed the detection of distinct stages of secretion occurring in a time frame of milliseconds. Exocytosis, by definition, now refers to a phase of secretion at which an electrical continuity of granule and PM prevails and the access of the granule content to the cell exterior is not impeded any more by a cellular membrane.
Before exocytosis, the granules undergo a "docking" reaction at specific release sites, which involves the binding of several granule- and PM-associated complementary proteins (see Ref. 101 for review). This is followed by a "priming" reaction, a process requiring metabolic energy and providing competence of docked granules for membrane fusion and exocytosis (41, 128, 215). A specific signal, e.g., an increase of cytosolic [Ca2+], stimulates exocytosis, which is then followed by the release of the granule matrix. The release of the granule matrix appears to be triggered by specific signaling molecules, temporally distinct from and also not obligatorily coupled to exocytosis (11, 23).
There is mounting evidence that cation and anion fluxes across granule
membranes occur via specific ion channels. This review is not a survey
of published literature on known properties and function of
intracellular ion channels. It does, however, describe recently cloned
ion channels with an intracellular localization, which are putative
candidates for secretory granule ion channels and could play a role in
exocytosis and release of secretory proteins. An overview is also given
of sensitive electrophysiological, optical, and microscopic techniques
with a high degree of temporal and spatial resolution and low
signal-to-noise ratio that are currently in use to study exocytotic
secretion. Finally, this review emphasizes recent biochemical and
biophysical studies in pancreatic acinar and insulin-secreting
-cells, which provide compelling evidence that ion flux through
granule ion channels is required for secretion to occur. This happens
by modulating the final steps of the secretory process, namely,
exocytosis and/or the release of macromolecular secretory products.
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BACKGROUND |
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Mechanisms of Regulated Protein Secretion
Secretory proteins (including precursor proteins such as proenzymes or proinsulin) are synthesized on the rough endoplasmic reticulum (RER) and inserted into the cisternae of the RER in statu nascendi. This is the only time they cross a cellular membrane. Thereafter, they are confined within membrane-bound cellular compartments. The secretory proteins are transferred from one compartment to the next by vectorial transport while undergoing several maturation steps, which are initiated in the Golgi network. Processing and sorting occur within the Golgi complex. Whereas the pH in the RER is near neutral (108), the trans-Golgi network has a pH of ~6.0-6.5 (57) because of active H+ pumping into the organelle by an electrogenic proton-translocating ATPase, the vacuolar-type H+-ATPase (V-ATPase) (71). Acidic pH is required if Golgi-localized enzymes involved in posttranslational modifications, such as sialylation, sulfation, and glycosylation, are to operate efficiently. The secretory granule is formed from the condensing vacuole, which buds off the trans face of the Golgi complex. The condensing vacuole is a membrane-bound organelle that contains secretory proteins in dilute form. It then undergoes a packaging process, during which its content is condensed by processes that are still poorly understood. Most secretory granules, including chromaffin and islet granules, gradually acidify through the activity of a V-ATPase (71). Once the granule has matured and has attained its highest density, it serves as a storage depot. The granules of exocrine acinar cells are exclusively found at the apex, which highlights the polarity of these cells (143). InChemiosmotic Hypothesis of Exocytosis
Almost 25 years ago, Pollard and collaborators (146, 151) proposed that anion conductances play a crucial role in Ca2+-dependent secretion. According to their chemiosmotic hypothesis of exocytosis, an H+-ATPase expressed in the secretory granule membrane actively pumps protons into the granule. Proton influx is electrically balanced by influx of anions, particularly of ClThis model was based on studies in chromaffin cells (146,
151). Reports in pancreatic islets supported Pollard and
coworkers' chemiosmotic hypothesis in so far as they observed a
Cl dependence of glucose-induced insulin release
(140, 184). In subsequent work on permeabilized adrenal
medullary cells, Knight and Baker (111) found that high
concentrations of Cl
could promote release of granular
protein in the absence of Ca2+. Ca2+-dependent
release, however, was inhibited by Cl
. These data were
therefore not consistent with the suggestion of Pollard and coworkers
that entry of Cl
into chromaffin granules promotes
exocytosis (see Ref. 21). Unfortunately, the discrepancies
regarding the role of Cl
in secretion of chromaffin cells
have not been followed up and resolved. The fact remains that
chromaffin granules are acidified by the action of a V-ATPase
(192), which necessitates a parallel conductance to shunt
its electrical current for efficient operation and is mediated by
either influx of anions or efflux of cations (12).
In exocrine glands, condensing vacuoles of pancreatic and parotid secretory granules were found to be acidic by quantification of the partition of a permeant weak base by immunoelectron microscopy (141). The internal pH of mature granules, however, may or may not be acidic. In one in vitro study, the intragranular pH of isolated pancreatic zymogen granules (ZG) was estimated to be ~6.5 with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) (81). This was confirmed in intact cells with the pH-sensitive fluorescent dyes acridine orange (56, 83, 137), LysoTracker (83), or quinacrine (208). This is also supported by the fact that the 31- and 70-kDa subunits of the V-ATPase are expressed in the membranes of rat pancreatic ZG (167). In contrast, evidence for a V-ATPase activity in secretory granules from exocrine glands is lacking (14, 15). Moreover, other studies in intact cells using the weak base 3-(2,4-dinitroanilino)-3'-amino-N-methyldipropylamine (DAMP) or the pH-sensitive fluorescent dyes acridine orange and LysoTracker red came to the conclusion that the pH of ZG is neutral (141, 185). Consequently, ZG acidification as a prerequisite for a chemiosmotic mechanism of exocytosis is still an unresolved matter.
In 1985, Stanley and Ehrenstein (186) proposed that an initial step in the process of exocytosis of neurosecretory granules is activation of Ca2+-dependent K+ channels present in granule membranes. In this model, salt influx into the granule is controlled by a K+ channel that opens when intracellular [Ca2+] is elevated as a result of receptor activation. Electrical coupling to anion pathways results in salt and water influx and osmotic swelling, followed by fusion of the vesicle membrane with the luminal membrane and release of the vesicle contents. This model was used to explain protein secretion in exocrine cells with granules, which may lack an active V-ATPase, such as ZG (79).
According to the models proposed by Pollard and coworkers (151) and by Stanley and Ehrenstein (186), increasing the extragranular tonicity should inhibit secretion (72). Evidence for this effect of osmolarity was, for instance, provided by Knight and Baker (111) in chromaffin cells whose PM had been permeabilized by dielectric breakdown with intense electric fields but also by Fuller et al. (79) in protein secretion studies using isolated pancreatic acini permeabilized with digitonin.
However, subsequent pioneering studies in beige mouse mast cells with electrophysiological (patch clamp) membrane capacitance measurements (40, 234) demonstrated that fusion actually precedes swelling, which proved that osmotic swelling is not required for fusion. Swelling did occur, but it took place after fusion of granules with the PM (40, 234). Both reports speculated that granule swelling was necessary to stabilize and widen the exocytotic pore and that swelling occurred by movement of extracellular small solutes through the exocytotic pore into the granule matrix (40, 234). These observations were taken as strong evidence to fully dismiss the swelling (= chemiosmotic) hypothesis of exocytosis.
The studies by Zimmerberg et al. (234) and Breckenridge and Almers (40) were published at about the same time as interest was developing in the cellular and molecular biology of protein factors mediating membrane fusion in yeast. This shifted the focus toward other mechanisms that might explain the membrane fusion process in eukaryotic systems and led to the identification of ubiquitously expressed and obligatory protein components of cellular fusion events. These include soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) proteins, Sec1/Munc18 homologs (SM proteins), and Rab proteins. These three classes of Ca2+-dependent and -independent docking and fusion proteins appear to be universally involved in intracellular fusion reactions, and enormous progress has recently been made in the understanding of their role in vesicle fusion. A thorough and detailed discussion of their components and function is not the scope of this review and can be obtained elsewhere (see, for example, Ref. 101).
Chemiosmotic Hypothesis of Exocytosis: An Obsolete Mechanism?
In 1988, Gasser, DiDomenico, and Hopfer (82) proposed that the fluidity of the pancreatic primary secretion is of paramount importance for the discharge of digestive proenzymes from exocytosed secretory granules. They argued that the fluidity of the primary secretion is also determined by the amount of electrolytes and water, which is secreted by acini. ClThus recent studies have led to a more differentiated reevaluation of
the chemiosmotic hypothesis of exocytosis. They indicate that a
chemiosmotic process may be operative at particular stages during the
sequence of events associated with protein secretion in exo- or
endocrine cells. Support for the model forwarded by Stanley and
Ehrenstein (186) has been obtained from studies on mucin
granules, which provide evidence for Ca2+-activated
K+ channels in the membrane of these granules
(136). This study implies that
Ca2+/K+ exchange in the granule matrix may
induce disaggregation and swelling of granules, possibly because of
K+ preventing protein condensation and binding of
aggregates to granule membranes (51). Further evidence
compatible with the importance of granule K+ channels for
secretion as proposed by Stanley and Ehrenstein (186) has
been obtained by Hoy et al. (97) in pancreatic -cells and by Jensen and collaborators (103) in renal
juxtaglomerular cells. Data in pancreatic
-cells (22,
24) are more in line with a critical role of granule
acidification and concomitant Cl
fluxes for the process
of exocytosis and insulin secretion, as originally implied by Pollard
et al. (151).
This new insight into a critical role of granule ion channels and ion fluxes for exocytosis and release of macromolecular secretory products has been made possible because of the recent availability of very sensitive techniques that allow us to study these complex processes in more detail. There is also increasing functional evidence for the presence of intracellular ion channels (for review, see Refs. 196, 227), which belong to several families of cloned ion channel proteins and also include putative intracellular ion channels.
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EXPERIMENTAL TECHNIQUES TO STUDY EXOCYTOSIS AND RELEASE OF SECRETORY PRODUCTS |
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A classic approach to study secretion involves the stimulation of a preparation of isolated cells or cell groups and measurements of the secreted proteins by radioactive metabolic labeling, ELISA, or enzymatic assays. This can also be done after permeabilization of the cells to gain access to the cytosol (79, 111, 226), thus providing some means of controlling intracellular processes and the cytosolic environment. However, these methods require large numbers of cells and offer little temporal resolution.
Three main approaches are currently used to study secretion from single cells: capacitance measurements that trace changes of the cell surface area due to membrane addition by exocytosis of secretory granules; electrochemical detection by oxidation or reduction of released transmitter molecules at the surface of a carbon-fiber electrode placed in close vicinity to the site of release; and optical techniques to monitor release, membrane addition, or pH changes.
Capacitance Measurements of Cell Surface Area
Granule fusion with the PM and membrane reuptake during exo- and endocytosis lead to an increase or decrease in the cell surface area and, correspondingly, in the cell's membrane capacitance (Cm) (135). Cm is proportional to its surface area with a specific capacitance of 10 fF/µm2 (135). The electrical continuity of granule and PM can thus be considered as an indicator of exocytosis. The average capacitance of pancreatic acinar andAny membrane that is added by exocytosis is detected as a capacitance
increase; endocytosis on the other hand removes membrane from the cell
surface and thus reduces the capacitance. This means that one problem
associated with Cm measurements is that they only report net changes of membrane surface, which do not necessarily reflect reliable estimates of the rate of secretion. In
-cells, this
will not influence the measurement of exocytosis because endocytosis
proceeds on a relatively slow time scale (66). However, Cm measurements may not be sufficient to
independently resolve these processes in cells in which a close
temporal coupling of exocytotic and endocytotic events prevails. This
concern is of particular importance in pancreatic acinar cells, which
secrete at a slower rate and for longer time periods than do
neuroendocrine cells. Recently, optical measurements of membrane
turnover have been developed, which use membrane-sensitive fluorescent
probes and can provide real-time measurements of secretory dynamics
(29, 30). This technique, in combination with
Cm measurements, allows for the independent
evaluation of exocytotic and endocytotic activity and reports spatial
information about these processes (182). The most widely
used probe is FM1-43, a fluorescent amphipathic styryl dye, which
rapidly and reversibly partitions into the outer leaflet of biological
membranes and becomes trapped in recycled vesicles on endocytosis. On
stimulation, preloaded vesicles release dye into the bathing medium and
fluorescence thereby declines (31). A study in rat
pancreatic acinar cells selected this approach by monitoring changes of
membrane surface area (Cm) in combination with
measurements of the membrane turnover using FM1-43
(86). This study revealed that exo- and endocytosis arise
within seconds after secretagogue-induced activation and coincide both
temporally and spatially (86).
After incorporation of the granule membrane into the apical cell
membrane, any granule conductance should contribute to the whole cell
conductance (Gm). Studies have aimed at
answering the question of whether fusion of individual granules with
the PM inserts granule channels into the cell membrane. These studies combined capacitance with single-channel measurements in the whole cell
configuration and attempted to correlate temporal changes in
Cm and Gm induced by
secretory stimuli. Studies carried out in rodent pancreatic acinar
cells have yielded controversial results, either claiming a
contribution of granular ion channels to increases in
Gm after secretory stimuli (126) or
not (172). However, the hypothesis tested by Schmid and
Schulz (172) and Maruyama et al. (126) that
granule exocytosis (Cm) and opening of
putative granule ion channels (
Gm) should
temporally overlap is not valid. The studies by Zimmerberg et al.
(234) and Breckenridge and Almers (40)
demonstrated that granule swelling (and thus release of secretory
products) lags significantly behind granule exocytosis. Similarly,
significant delays between
Cm and discharge
of secreted macromolecules were recently reported in mast cells
(225) and pancreatic
-cells (23). If the
assumption that activation of granule ion channels promotes the release
of secreted macromolecules is correct, then an increase of
Gm (induced by opening of granule ion channels)
will occur after a change in Cm. This change of Gm may be difficult to resolve within the large
increase of whole cell Gm (reflecting activities
of Cl
channels in the PM). One additional problem with
the negative study (172) was also the choice of a
nonphysiological stimulus [guanosine
5'-O-(3-thiotriphosphate); GTP
S], when a physiological Ca2+-dependent agonist, such as acetylcholine (ACh) or
cholecystokinin (CCK), would have been appropriate.
Amperometric Detection of Released Molecules
Electrochemical detection is based on the oxidation or reduction of released endogenous or preloaded molecules (46, 223). In the case of preloading of molecules, the tracer (an easily oxidized molecule such as serotonin) is taken up into the granules. It is subsequently cosecreted with stored macromolecules (e.g., insulin), which are not sufficiently "electroactive," i.e., they are oxidized so slowly at the electrode that they are not detectable and therefore not useful to be used as tracer molecules (for more recent technical developments and for measurements of macromolecule release on a millisecond time scale, see, however, Refs. 98, 222). A positively charged carbon fiber electrode placed next to the cell will then detect exocytotic events as current spikes due to oxidation of the tracer molecule by the electrode. The oxidation current is a direct measure of release and is not susceptible to interference from endocytosis. The cell is not subject to whole cell dialysis and "washout" of diffusible cytoplasmic constituents. The amperometric method was previously applied to measurements of secretion in pancreaticAlthough both capacitance and electrochemical techniques allow measurements of single-vesicle fusion to be performed with a time resolution of milliseconds, these techniques suffer from two major drawbacks. Their spatial resolution is low (as with whole cell Cm measurements or large-diameter carbon fiber electrodes with 5- to 8-µm tip diameter). Moreover, they do not provide information on the steps before membrane fusion or after endocytotic uptake of membrane, because they only measure membrane addition or release, respectively.
Evanescent Wave Microscopy
The technique of evanescent wave or total internal reflection fluorescence microscopy (TIR-FM) offers a compromise between electron microscopy, which offers only "snapshots" of the exocytotic process, and Cm and amperometric techniques in that good spatial and temporal resolution can be achieved.TIR is based on Snell's law of optics: If light traveling in a dense
medium (e.g., a glass coverslip with a high refractive index,
n1) hits a less dense medium (e.g., an aqueous
medium of lower refractive index, n2), beyond a
certain "critical angle," c, the light will undergo
TIR. This critical angle depends on the relative refractive indexes of
the two media. If the
n2-to-n1 ratio is very
small, the critical angle is shallow (
c = 24.6°) and TIR is readily achieved.
In practice, cells are grown on glass coverslips or transparent
materials of high refractive index, and a beam of light, usually from a
laser, is optically coupled into the coverslip by a prism or the
objective itself. If light approaches the aqueous medium at
>c, it totally reflects into the glass. However, at
angles >
c, some of the energy slightly penetrates the
aqueous medium as an "evanescent wave," propagating parallel to the
interface, which can be derived from Maxwell's equations on the
behavior of electromagnetic fields at a dielectric interface (18,
20). An important property of the evanescent wave is that the
intensity falls off exponentially away from the coverslip. The
"penetration depth" (the distance where the intensity I has
decreased to Io/e, where Io is
intensity at distance o and e is natural
logarithm) depends on the incidence angle, wavelength, and polarization
of light, as well as the refractive index of the coverslip and the medium. Penetration depths of <100 nm are achieved without
difficulty. Thus only fluorophores near the coverslip are excited.
TIR-FM illuminates vertical slices with the dimensions of a thin
electron microscopy section (<100 nm) as opposed to slices of
~500-800 nm for one- and two-photon confocal systems,
respectively. This thin optical sectioning means that the
signal-to-noise ratio is much better than with confocal images and
cellular photodamage and photobleaching are minimal.
TIR-FM is a complementary approach that can be combined with other microscopy techniques, such as brightfield, epifluorescence, confocal, or atomic force microscopy (AFM) (see Atomic Force Microscopy). TIR-FM applications in cell biology have been expanded to studies of secretion (94, 104, 119, 139, 165, 188, 189, 210) by the recent advent of green fluorescent protein (GFP) of the jellyfish Aequorea victoria for more specific staining of secretory organelles and its cyan, yellow, and red derivatives (CFP, YFP, and RFP, respectively). When linked to granular proteins and expressed in cells, it retains its fluorescence properties and can therefore be used as a granule marker (105, 119, 153). Like acidotropic dyes, e.g., acridine orange or dyes of the LysoTracker LysoSensor families, it is released with the granular contents after membrane fusion such that secretion is observed as a decrease in fluorescence. Recently, pH-dependent GFP mutants have become available (131). Further improvement of TIR-FM has also been accomplished by the recent introduction of new objective lenses and condensers (19).
Atomic Force Microscopy
In AFM, a fine silicon or silicon nitride tip scans the surface of the sample. Any deflection of the tip due to surface topography is recorded. The AFM provides three-dimensional data of biological samples with a lateral or x,y-resolution in the range of 50-100 nm and with a height or z-resolution in the range of ~1 nm! One advantage of AFM as opposed to conventional electron microscopy is that it allows the study of the morphology of living cells or organelles under physiological conditions in real time (175). AFM has been used to study membrane dynamics, such as exo- or endocytosis on living cells, or the swelling behavior of isolated secretory granules. In rat pancreatic acinar cells, discrete areas of transient exocytosis have been detected when imaged by AFM (176). By probing the outer surface of acinar cells large, craterlike areas or "pits" (diameter 0.5-2 µm) were only found at the apical surface, where regulated secretion took place. Inside the pits, "depressions" of ~150-nm diameter were identified, which presumably represent the docking and fusion sites of ZG that are ready to fuse with the PM [corresponding to the "readily releasable pool" (RRP) of secretory vesicles in neuroendocrine cells]. After the cells were stimulated, the diameter of the depressions increased within 5 min and returned to the initial size after a further 20 min. The increase and decrease of the diameter of the depressions correlated well with the amount and kinetics of amylase secretion (176). Hence, exocytotic secretion appeared to be very slow (with a time frame of minutes) compared with neuroendocrine cells. The reversible changes of the diameter of the depressions suggested that the ZG transiently fuse with the PM. They then release their content into the extracellular space via a fusion pore before the "empty" granules are retrieved intact from the PM (the kiss and run or "transient fusion" mechanism) (Refs. 5, 13, 41; see also Refs. 86, 172). This differs from a mechanism of endocytosis occurring by a separate process after complete incorporation of the secretory granule membrane into the PM ("full fusion").Jena et al. (102) asked how the ZG morphology associated
with kiss and run recycling could be maintained during secretion. They
argued that ZG diameter should decrease during amylase secretion and
therefore, as a consequence of Laplace's law, ZG surface tension should increase. An increase of ZG surface tension should further enhance enzyme release, which should therefore decrease ZG dimensions until total collapse of the granule. However, full fusion does not
occur according to their observations (176). To clarify
this issue, they used AMF in combination with confocal microscopy to study the three-dimensional dynamics of isolated ZG during stimulation (102). Exposure of ZG to GTP, but not GDP, increased their
height by 15-25% as measured by AFM. A comparable increase in
diameter was determined by confocal microscopy. Similar effects were
observed with NaF. An active mastoparan analog (Mas7) known to
stimulate Gi proteins increased ZG GTPase activity and also
induced swelling. Mas7, NaF, and GTP increased vesicle swelling to a
similar extent, suggesting that ZG-associated heterotrimeric
GTP-binding proteins (Gi3 based on
immunoblots of ZG membrane fractions) participate in regulating ZG
size. Moreover, the effects of Mas7, NaF, and GTP on ZG size occurred
in the presence of KCl, but not when KCl was replaced by cyclamide,
suggesting that swelling of ZG may be mediated by ion flux through
K+ and Cl
channels in the granule membrane
(102). Interestingly, 100 µM Ca2+ or 200 µM EGTA had no effect on ZG size [see Expression of a Ca2+-activated and bicarbonate-permeable anion channel
(CLCA)]. On the basis of these AFM studies in pancreatic acinar
cells and isolated ZG, Jena and coworkers (102) proposed that
K+ and Cl
channels in the granule membrane
are required to induce granule swelling during secretion to prevent ZG
collapse. Ion fluxes through K+ and
Cl
channels in the granule membrane and osmotic swelling
thus appear to maintain granule integrity and morphology as a
prerequisite for kiss and run recycling (102, 175, 176).
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CLONED MAMMALIAN INTRACELLULAR ION CHANNELS |
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ClC Cl Channels
ClC-2.
A whole cell patch-clamp study on Cl channel activity in
pig pancreatic acinar cells provided the first evidence that a ClC channel might function as an intracellular Cl
channel
(42). The Cl
current was activated by strong
hyperpolarization and cell swelling, which are biophysical properties
reminiscent of ClC-2. This anion current also shared the
Cl
> I
selectivity sequence with
other ClC proteins. Immunohistochemical localization with a ClC-2
antibody revealed expression in both apical PM and ZG, suggesting that
it may operate as a Cl
efflux pathway in pancreatic
acinar cells and remain functional in the PM after exocytosis, thus
contributing to primary salt secretion. Subsequently, expression of
ClC-2 in both rat pancreatic plasma and ZG membranes has been confirmed
by immunoblotting (unpublished observations). Functional studies in
isolated ZG have recently identified a largely
Ca2+-independent Cl
conductance in isolated
ZG that could represent ClC-2 and may contribute to granule swelling
[see Expression of a Ca2+-activated and
bicarbonate-permeable anion channel (CLCA)].
ClC-3.
Several studies have suggested that ClC-3 may be the major candidate
for the volume-regulated Cl channel,
ICl-swell (60, 61), but this has
not remained uncontested (122). In contrast, a recent
study provides compelling evidence that this channel plays a critical
role in acidifying synaptic vesicles. Stobrawa et al.
(190) reported a phenotype associated with targeted
inactivation of the murine clcn3 gene. The mice exhibited
postnatal growth retardation, blindness secondary to progressive
retinal degeneration, and behavioral abnormalities associated with
hippocampal degeneration. Further investigations revealed that ClC-3 is
present on synaptic vesicles and participates in their acidification.
This occurs through active proton pumping by an electrogenic V-type
H+ pump. In the absence of a conductive pathway, the
generation of an inside-positive potential difference across the
vesicle membrane will limit the degree of acidification that can be
achieved by the pump. The dissipation of this voltage by an electrical shunt allows for higher rates of proton transport. Indeed, biophysical studies have revealed Cl
conductances in many
intracellular organelles, including the endoplasmic reticulum (ER),
Golgi, vesicles of the exocytotic and endocytotic pathways, lysosomes,
and synaptic vesicles (3, 196, 227). Their acidification
serves various purposes, such as modulation of enzymatic activities,
processing of prohormones, differential sorting of receptors and
ligands, endocytosis, and other vesicle trafficking. The
electrochemical proton gradient also provides the driving force for the
transport of other substances across the vesicle membrane as in the
concentrative uptake of neurotransmitters into synaptic vesicles, e.g.,
of glutamate (127).
ClC-5.
The Cl channel ClC-5 shares the Cl
> I
selectivity with other ClC channels. Mutations
encountered in Dent's disease, a rare familial disorder, reduce or
abolish Cl
currents associated with the functional ClC-5
cDNA in the Xenopus laevis oocyte expression
system. This disease is associated with low-molecular-weight
proteinuria and hypercalciuria; thus ClC-5 may mediate renal protein
endocytosis. Indeed, ClC-5 knockout mice exhibiting a targeted
disruption of the murine clcn5 gene showed impaired proximal
tubule protein absorption and reduced receptor-mediated and fluid-phase
endocytosis in proximal tubular cells (150, 220). After
budding from the PM, endocytotic vesicles are progressively acidified
on their way to the lysosomes, and ClC-5 may provide a rate-limiting
anion conductance for efficient endosomal acidification in the proximal
tubule (150, 220). However, ClC-5 expression in X. laevis oocytes or mammalian cells elicits strongly outwardly
rectifying Cl
currents that can be detected only in a
voltage range more positive than +20 mV (75). However,
such an inside-positive membrane potential is highly unlikely in
intracellular compartments. Moreover, ClC-5 expressed in X. laevis oocytes or mammalian cells is inhibited by extracytosolic
acidic pH (174). These properties cast doubt on ClC-5
being solely responsible for Cl
conductance in renal
endosomes because Cl
movement into the acidifying
compartment would be greatly limited. This suggests that endosomal
anion conductance requires additional transport pathways and/or that
ClC-5 displays different properties in situ because of the presence of
regulatory subunits.
ClC-7.
Osteoclastic bone resorption requires extracellular proton accumulation
(198). Osteoclasts are multinucleated cells formed by the
fusion of mononuclear hematopoietic stem cells belonging to the
phagocyte series. When attached to bone, osteoclasts create lacunae,
into which protons and acid hydrolases are translocated to digest
mineralized bone matrix. Acid secretion is mediated by the fusion of
internal vesicles containing V-type H+ pumps into the
osteoclast surface membranes adjacent to the bone surface, creating the
"ruffled border" where bone resorption occurs. The extracellular
acidic lacunae require fluxes of counterions, e.g., of
Cl through Cl
channels for charge
compensation. A recent report by Kornak et al. (113)
defined the role of the ClC-7 channel protein in osteoclast-mediated bone resorption by studying clcn7-deficient mice.
Inactivation of ClC-7 caused a severe phenotype with osteopetrosis
(bone petrification) and retinal degeneration. The defects of skeletal
morphogenesis could all be explained by impaired osteoclastic bone
resorption. Osteoclasts in ClC-7-deficient mice exhibited poorly
developed ruffled borders and did not form resorption lacunae.
Immunohistochemical staining for ClC-7 in normal osteoclasts
demonstrated intracellular staining of late endo-/lysosomal
compartments as well as localization along ruffled border membranes
similar to the distribution of the V-type H+-ATPase, which
is consistent with a distribution of ClC-7 in subplasmalemmal secretory
vesicles and in the PM. Further functional studies demonstrated a
defect in extracellular acidification by osteoclasts at the PM, but no
deficient late endo-/lysosomal or lysosomal acidification was observed
(113). This indicates that ClC-7 is not solely responsible for the acidification of late endosomes and may also involve other anion channels, such as p62 (171) (see CLIC/p64
Cl
Channels). Interestingly, a recent in situ
hybridization study showed that ClC-6 and ClC-7 are strongly expressed
in mouse pancreatic acinar cells but not in islets (107),
suggesting that these channel proteins may also operate as
intracellular anion channels in acinar cells, but their intracellular
localization and physiological function is currently unknown.
CLIC/p64 Cl Channels
Recently, several related human genes that share homology with the
COOH-terminal half of bovine p64 have been cloned. These genes
constitute a protein family called CLIC (Cl intracellular
channel). The CLIC/p64 superfamily has grown to include p64 itself, the
p64-like protein parchorin (138) and five CLIC proteins.
The first CLIC member to be identified, CLIC1/NCC27, was originally
detected in cell nuclei (214) and was subsequently shown
to be enriched in the brush border of proximal tubule cells (211). So far there is no evidence that CLIC2, CLIC3, and
CLIC5 are expressed in secretory vesicles (28, 95, 154).
CLIC4/huH1 was recently identified (64) as the human
homolog of a rat brain protein termed p64H1 (47, 62).
CLIC4 mRNA is widely expressed in neuronal and nonneuronal tissues.
Although rat brain p64H1, which encodes for a 28.6-kDa protein,
colocalized with markers for the ER of transiently transfected rat
hippocampal HT-4 cells (62), in another study it was
localized to the large dense-core vesicles of rat hippocampal neurons
(47).
Indirect immunofluorescence, cell fractionation, and immunoblotting studies have localized native and recombinant CLIC4 proteins both to the cytosol and to intracellular membranes. A similar, very unusual, dual localization is characteristic of many CLIC and p64-related proteins (47, 64, 70, 138, 154, 160, 214). For example, human CLIC4 is enriched in the apical region of proximal tubule cells but partly colocalizes with caveolae in a pancreatic cell line (64). In addition, the mouse homolog of CLIC4, called mc3s5/mtCLIC, was recently localized to the mitochondria and cytoplasm of keratinocytes (70). Such a protein distribution could reflect a shuttling of CLIC4 between the cytoplasm and different endomembrane systems (including secretory vesicles, mitochondrial membranes, and caveolae) and an involvement of the protein in widespread cell biological processes such as membrane trafficking or vesicle transport.
Various electrophysiological studies have shown that several members of
this gene family, including bovine p64 (65, 116, 117),
CLIC1 (214), CLIC3 (154), and rat brain
p64H1/CLIC4 (62), play a role in Cl
transport. Cells overexpressing recombinant CLIC4 contain intracellular anion channel activity that is absent from mock-transfected cells (62). There are several alternative ways in which CLIC
proteins could be linked to intracellular ion channel activity. They
could be channel-forming proteins, they could activate endogenous ion channels (either directly or indirectly), or they could perform both
functions. The "ion channel" hypothesis has been tested directly for CLIC1, which forms channels after being incorporated, as a pure
recombinant protein, into planar bilayers (212). Although it has yet to be shown that this channel activity in vitro corresponds to an endogenous ion channel, it is clearly possible that CLIC1 and
other CLIC proteins might have a direct role as intracellular ion
channels. An alternative hypothesis is that some or all of the CLIC
proteins are anion channel regulators, rather than (or as well as) ion
channels. Several CLIC proteins are also expressed in endomembranes,
which are not associated with acidic compartments (62, 64, 211,
214). This suggests that the role of CLIC proteins may not be
restricted to its operation as a shunt pathway for electrogenic
V-ATPases. However, as long as knockout animals for the various CLIC
proteins are not available, the exact function of these proteins
remains difficult to establish.
CFTR Cl Channel
Studies using isolated tissue from control and CF submandibular
salivary glands (129) showed that -adrenergic agonists
were able to stimulate the release of mucin and amylase from control tissue, but the secretory responses of CF tissues were reduced by
~60%. No differences were found between the total mucin pools of
control and CF tissues. Similar observations were made in CFTR knockout
mice (132). In these studies, release of
[14C]glucosamine-labeled mucins from mouse submandibular
glands was monitored in response to activation of the cAMP-mediated
second messenger cascade. Although a large, sustained release of mucin was observed in control mouse tissue, the stimulated release of mucin
from CFTR knockout mouse tissue was significantly reduced (132).
The regulation of mucin secretion by CFTR has also been assessed in airway epithelial cells. Mergey et al. (130) studied the release of mucin after incorporation of [14C]glucosamine into mucins. Stimulation of immortalized normal human airway epithelial cells, with either isoproterenol or forskolin, led to a 40% increase in mucin release. In contrast, stimulation of immortalized CF airway cells resulted only in a 1-3% increase in mucin release. The defective cAMP-mediated regulation of mucin secretion was restored after adenovirus-mediated gene transfer of wild-type CFTR to these cells. Granule exocytosis and mucin release in airway epithelial cells were also monitored by release of previously internalized fluorescein isothiocyanate (FITC)-dextran, a fluid-phase endocytosis marker, and by increases in Cm measured with whole cell patch clamp (179). Treatment of non-CF airway cells with a membrane-permeant cAMP analog resulted in a significant increase in Cm, consistent with net incorporation of membrane into the cell surface. Simultaneous release of FITC-dextran in response to the cAMP analog suggested that the cAMP-dependent increase in Cm is partly caused by fusion and incorporation of exocytotic vesicles into the PM. Under identical experimental conditions, stimulation with the cAMP analog had no effect on either Cm or discharge of internalized marker in airway cells derived from a CF patient (179).
Mucin secretion has also been studied in gallbladder epithelium, a
model system for mucus secretion by columnar epithelial cells
(115). Mucin granules released mucus by merocrine
secretion in mouse gallbladder epithelium when examined by transmission electron microscopy. Immunofluorescence microscopic studies revealed intracellular colocalization of mucins and CFTR (115). The
data in submandibular, airway, and gallbladder epithelia strongly
suggest that CFTR Cl channels are present in mucin
granule membranes and support a model according to which CFTR-mediated
influx of Cl
into the granule enhances secretion by
modulating fusion, exocytosis, and/or release of mucus.
KCNQ1 (KvLQT1) K+ Channel
KVLQT1 (KCNQ1) is a very low-conductance (<1.5 pS) voltage-gated K+ channel distributed widely in epithelial and nonepithelial tissues (for review, see Refs. 32, 164). KCNQ1 was found to be mutated in the hereditary cardiac disease long QT syndrome 1 (219). In the heart and inner ear, KCNQ1 coassembles with a ![]() |
SECRETORY GRANULE ION CHANNELS AND REGULATED SECRETION |
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Pancreatic Zymogen Granules
Background.
Secretion by the exocrine pancreas is carried out by two
morphologically and functionally distinct epithelia, the acini and ducts. Acinar cells secrete a plasmalike primary fluid together with
digestive enzymes, which are stored as proenzymes in ZG at the apex of
the cells. The primary fluid is modified by the downstream duct cells,
which generate the HCO
|
Expression of a Ca2+-activated and
HCO > Cl
selectivity profile, a linear
current-voltage relationship, and a 25-pS single-channel conductance,
which can be blocked by DIDS or the reducing agent dithiothreitol (DTT)
(50). So far there had been no evidence to suggest an
intracellular localization of CLCA channels, but using in situ
hybridization techniques, Gruber et al. (90) demonstrated
the expression of CLCA mRNA in mouse pancreatic acini.
Expression of chromanol-sensitive K+ channel KCNQ1. Two monovalent cation conductive pathways contribute to K+ fluxes into ZG. A nonselective monovalent cation conductive pathway is equally permeant to K+ and Na+ and blocked by flufenamic acid (200). The K+-selective conductive pathway is blocked by ATP and Glib (38, 200, 202) and thus appears to be similar to ATP-sensitive K+ (KATP) channels (2, 100, 209). However, Kir6.2, the pore-forming subunit of KATP channels, is not expressed in rat pancreatic acini (194). KCNQ1 (KvLQT1) may be a candidate for the ZG K+ channel. In situ hybridization studies have shown that KCNQ1 and KCNE1 are expressed in rodent pancreatic acini (58, 114, 197). Moreover, KCNQ1, which is the apical K+ channel required for active K+/H+ exchange and stimulated HCl secretion by gastric parietal cells, has also been detected in intracellular organelles of parietal cells, the tubulovesicles (87). In epithelial tissues, KCNQ1 K+ channels are activated by cAMP or Ca2+ and selectively inhibited by the chromanol 293B (32, 191, 228).
In rat pancreatic acini, 293B (10 µM) completely inhibited K+ conductance, whereas the nonselective and ClRegulatory proteins of ZG ion conductive pathways.
The regulation of ZG K+ and Cl conductance
pathways by ATP and Glib is reminiscent of members of the
ATP-binding cassette (ABC) superfamily of transporters,
which are either ion channels or channel regulators (4,
178). Specific antibodies (JSB1, C219) against cytosolic domains
of the ABC transporter multidrug resistance P-glycoprotein
(MDR1/PGY1/ABCB1) blocked ZG Cl
conductance and bound to
a 65-kDa protein of ZG membranes (200, 207). Subsequently,
immunoblots were performed and K+ and Cl
conductive pathways were characterized in isolated ZG from control and
mdr1 knockout mice (204). The experiments provided
evidence that this protein is a mdr1 gene product
possibly a spliced
or truncated variant
that inhibits ZG K+ and activates
Cl
conductance (Ref. 204; see also Ref.
216 for the role of MDR1 as a regulatory protein). A
65-kDa [3H]Glib binding protein [dissociation constant
(Kd)
6 µM] has also been identified
in ZG membranes (38). However, it is not known
whether the 65-kDa mdr1-like gene product and the 65-kDa [3H]Glib receptor of ZG membranes are identical. A
high-affinity receptor for a derivative of dihydropyridine
(34) has also been purified, which selectively regulates
the K+ conductance in ZG (39). This protein
is identical to ZG-16p, a recently cloned ZG protein with no known
function (49). Interestingly, ZG-16p is enriched in
rafts, cholesterol/glycosphingolipid-rich membrane microdomains, and
the disruption of the latter by cholesterol depletion enhances
stimulated amylase secretion (173). This observation is
compatible with the hypothesis that ZG-16p operates as an inhibitor of
the ZG K+ channel and that this channel plays a critical
role in controlling regulated secretion (39). It also
suggests that ZG ion channels and their regulators may be
clustered in lipid rafts (see, for example, Ref.
125).
ZG K+ conductance and pancreatitis. Studies in goblet cells indicated that opening of Ca2+-sensitive K+ channels of secretory granules causes K+ influx, which by exchanging with Ca2+ bound to the granule polyanionic matrix results in decondensation and disaggregation of the matrix and granule swelling (136). This concept could be relevant to the pathophysiology of certain forms of hyperstimulatory acute pancreatitis with abnormally elevated cytosolic [Ca2+] (158). Abnormal Ca2+ signals may enhance fusion of granules with acidic lysosomes, resulting in vacuole formation and activation of trypsinogen (159, 187). Concurrent Ca2+-dependent opening of ZG K+ channels and K+ influx before fusion with the PM, intracellular swelling, and lysis of ZG in situ could fuel acinar autodigestion by increasing intracellular release of digestive proenzymes.
The membrane of ZG appears to be equipped with two cation and two anion conductance pathways, which contribute to K+ and ClPancreatic -Cell Granules
Background.
Insulin is produced in the -cells of the islet of Langerhans, where
it is stored in secretory granules until its release into the
bloodstream by regulated exocytosis.
-Cells are electrically active
and use this property to sense elevated blood levels of metabolic fuels
and to couple them to insulin release. Nutrient-stimulated secretion
involves two arms of signal transduction. One arm is dependent on
modulation of the KATP channel in the PM by glucose metabolites. The other arm involves intracellular metabolism of long-chain acyl-CoA in the tricarboxylic acid cycle and generation of
excess metabolic products, which promote exocytosis and release of
insulin through as yet unknown mechanisms (48, 53).
A 65-kDa mdr1-like sulfonylurea-binding protein that regulates
exocytosis.
To elucidate the mechanisms underlying the direct stimulatory effect of
sulfonylureas on the exocytotic machinery, Barg et al.
(24) measured exocytosis under voltage clamp conditions, which circumvents sulfonylurea-mediated depolarization of the cell.
Ca2+ and test substances were dialyzed into the
intracellular space through the recording electrode. Exocytosis and
discharge of granule contents were determined by combining measurements
of Cm and amperometric detection of released
serotonin. Stimulation of exocytosis by the sulfonylurea tolbutamide
was observed slightly above the resting [Ca2+] or by a
stepwise increase in [Ca2+] caused by photorelease of
caged Ca2+. Pharmacologically, the exocytotic mechanism
affected by tolbutamide was very similar to the -cell PM
KATP channels, because it was inhibited by diazoxide but
not by pinacidil, which activates cardiac/vascular KATP
channels by binding to the SUR2A/B (ABCC9) sulfonylurea receptor (181). KATP channels are physiologically
activated by increasing the ADP-to-ATP ratio and thus reduce cellular
depolarization and insulin secretion (63, 106, 133). ADP
applied through the recording pipette also inhibited
Ca2+-dependent exocytosis, and this could be reversed by
coapplication of tolbutamide. Together, the data indicated the
involvement of a SUR1 (ABCC8)-like regulatory mechanism in
-cell
exocytosis. Evidence for a mechanism similar to that in ZG, where a
65-kDa mdr1 gene product confers the modulation by sulfonylureas
(38, 202), was obtained in islet
-cells as well. First,
antibodies against cytosolic domains of ABCB1 (mdr1) (JSB-1 and C219)
detected a protein of 65 kDa in
-cell granule membrane fractions. In
addition, ultraviolet cross-linking revealed binding of the
sulfonylurea Glib to a protein of ~65 kDa in the granule fraction
(Ref. 24; unpublished observations). Also, intracellular
application of the ABCB1 antibody JSB-1 abolished the stimulatory
action of sulfonylureas on exocytosis. Finally, a blocker of ABCB1,
tamoxifen (110), prevented the stimulation of exocytosis
induced by tolbutamide. Together, the data suggested that sulfonylureas
bind to a granule membrane protein of 65 kDa, which may be an ABCB1
(mdr1) gene product. This leads to the activation of the exocytotic
machinery, possibly via opening of ion channels in the granule membrane
(see Fig. 2).
|
Expression of a ClC-3 Cl channel.
In analogy to KATP channels, it is conceivable that the
65-kDa
-cell granule sulfonylurea-binding protein represents a
regulatory subunit of a K+ channel, and evidence for this
has been obtained in pancreatic
-cells (97). However,
this is not likely in
-cells, because Ca2+-dependent
exocytosis in the presence or absence of tolbutamide was unaffected by
replacing intracellular K+ with Cs+ but
strongly inhibited by the Cl
channel blocker DIDS
(22) or by replacing intracellular Cl
with
glutamate. This is different from data obtained in chromaffin cells, in
which Ca2+-dependent secretion occurs in the presence of
glutamate but is inhibited by Cl
(111). The
data therefore suggested that intracellular Cl
fluxes are
involved in exocytosis in
-cells. Barg and coworkers (22) found that two antibodies against the
Cl
channel ClC-3 labeled
-cell granules. Immunoblot
analysis of
-cell homogenates and a granule fraction of the INS-1
cell line revealed an immunoreactive band with a molecular mass of
~90 kDa, as expected for the nonglycosylated form of ClC-3.
When a functional antibody against the COOH-terminal cytosolic domain
of ClC-3 was dialyzed into the intracellular space through the
patch-clamp electrode, exocytosis was strongly inhibited. This
interaction with the exocytotic machinery was specific, because a
nonfunctional antibody against the NH2-terminal domain of
ClC-3 was without effect (22). The authors therefore
concluded that granule Cl
flux carried by ClC-3 channels
is required for Ca2+-dependent exocytosis in
-cells.
This dependence of exocytosis on cytosolic Cl
does not
seem to be limited to the
-cell, because it is also required for
hormone release in a variety of other cells, including pancreatic
acinar cells (79) and pituitary melanotrophs
(168).
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PERSPECTIVES |
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Further studies combining appropriate highly sensitive techniques with specific molecular tools, such as genetically modified animal and cellular models, will be necessary to define with certainty the role of secretory granule ion channels and their regulatory proteins for exocytosis and release of secretory products. From a postgenomic perspective, however, the identification of secretory granule ion channels and the characterization of their physiological significance could gain importance for the development of therapeutic drugs controlling secretory events. This is particularly relevant because secretory granules, similar to other intracellular organelles, seem to be equipped with specific sets of ion channels, which represent ideal targets for the development of drugs with high tissue and/or cell specificity and a selective mode of action. In contrast, docking and fusion proteins involved in exocytosis are ubiquitously expressed and regulate exocytosis by more general mechanisms. They are therefore less well suited as targets of drug action. The use of putative therapeutic drugs as activators or inhibitors of secretory granule ion channels could significantly contribute to the improvement of pathophysiological disease conditions, such as NIDDM, acute pancreatitis, or CF.
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ACKNOWLEDGEMENTS |
---|
I thank Dr. Patrik Rorsman and collaborators (University of Lund, Sweden) for their interest in my work and support and Dr. Adam Szewczyk (Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland) for valuable comments.
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FOOTNOTES |
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Work in my laboratory has been funded by Grants from the Deutsche Forschungsgemeinschaft, the German CF Foundation (Deutsche Mukoviszidose e.V.), and the Novo Nordisk Foundation.
Address for reprint requests and other correspondence: F. Thévenod, School of Biological Sciences, Univ. of Manchester, G.38 Stopford Bldg., Oxford Rd., Manchester M13 9PT, UK (E-mail: frank.thevenod{at}man.ac.uk).
10.1152/ajpcell.00600.2001
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