1 Laboratory of Physiology, CME/VIB04, K.U. Leuven Campus Gasthuisberg O/N,
Herestraat 49, B-3000 Leuven, Belgium
2 Laboratory for Neuronal Membrane Trafficking, CME/VIB04, K.U. Leuven Campus
Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium
* Author for correspondence (e-mail: Jan.Parys{at}med.kuleuven.ac.be)
Accepted 7 January 2003
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Summary |
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Key words: Calcium stores, Calcium, Cytoskeleton, Protein kinase C, Intracellular calcium channel
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Introduction |
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Ca2+ signals evoked by agonist stimulation have complex temporal
and spatial characteristics, and the underlying mechanisms are not yet fully
understood (Berridge et al.,
1998). The differential regulation of the IP3R isoforms
by various modulators of IP3-induced Ca2+ release, such
as IP3, cytosolic Ca2+, ATP, calmodulin and
phosphorylation by several kinases, may contribute to this intricate pattern
(Patel et al., 1999
). There is
evidence that global responses, such as Ca2+ waves and
oscillations, are generated by the recruitment of a threshold number of
Ca2+ puffs (Bootman and
Berridge, 1995
; Marchant and
Parker, 2001
; Van Acker et
al., 2000
). Ca2+ puffs themselves can provide highly
localized signals leading to activation of specific phenomena such as muscle
relaxation in smooth muscle cells (Nelson
et al., 1995
). The intracellular localization of the
Ca2+ channels plays an important role in these processes because
the subcellular distribution of the puff sites determines the spatial pattern
of the Ca2+ signals.
The distribution of IP3Rs is dependent on isoform and cell type
as recently shown in, for example, pancreatic and salivary gland cells
(Lee et al., 1997;
Zhang et al., 1999
), oocytes
(Fissore et al., 1999
), aortic
smooth muscle cells (Tasker et al.,
2000
) and aortic endothelial, adrenal glomerulosa and COS-7 cells
(Laflamme et al., 2002
).
Differences in properties and distribution of IP3R isoforms can
therefore determine the cell-specific pattern of the Ca2+ signals
(Hirata et al., 1999
).
Moreover, a particular isoform can have multiple locations in a cell. In
myotubes of cultured mouse muscle, for example, IP3R1 is localized
in both the perinuclear region and at the I band of the sarcoplasmic reticulum
(Powell et al., 2001
).
Finally, the localization of IP3Rs can change in response to
Ca2+ elevations (Wilson et al.,
1998
). In RBL-2H3 cells, IP3R2 forms large clusters
after treatment with Ca2+-mobilizing agents. This redistribution
required a sustained Ca2+ influx, but the precise mechanism is not
yet understood. An increase in cytosolic Ca2+ concentration can
also affect ER structure (Subramanian and
Meyer, 1997
; Wilson et al.,
1998
).
Cytoskeletal elements, such as microtubuli and microfilaments, can also
contribute to the maintenance of local Ca2+ spikes and can
determine the position of the Ca2+-release apparatus via a local
organization of the ER (Fogarty et al.,
2000). Furthermore, the cytoskeleton can change rapidly in
response to extracellular signals (Keenan
and Kelleher, 1998
). PKC, which is activated after agonist
stimulation (Nishizuka, 1988
),
has recently been found to have a substantial effect on the microtubules. In
neuronal growth cones, activation of PKC resulted in a rapid growth of the
microtubules (Kabir et al.,
2001
).
In this study, we investigated the intracellular localization of
IP3R1 and IP3R3 in A7r5 vascular smooth muscle cells.
A7r5 cells have been used as a model system for studying IP3R1
function (Missiaen et al.,
1996; Missiaen et al.,
1998
). It also was recently found that IP3-induced
Ca2+ release, capacitative Ca2+ entry and proliferation
in A7r5 cells predominantly depended on the type 1 isoform
(Wang et al., 2001
). We found
that IP3R1 and IP3R3 were differently localized in these
cells. Moreover, after prolonged agonist stimulation, an intracellular
redistribution of IP3R1 but not of IP3R3 was observed.
This redistribution was dependent on PKC activation and the integrity of the
microtubular network, and occurs most probably via vesicle trafficking.
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Materials and Methods |
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Cell culture
A7r5 (ATCC CRL 1444) is an established cell line derived from embryonic rat
aorta. These smooth muscle cells were grown in 9% CO2 at 37°C
in Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum,
0.9% (v/v) non-essential amino acids, 3.8 mM L-glutamine, 85 IU/ml penicillin
and 85 µg/ml streptomycin.
Transfection
For transfection experiments, cells were seeded in two-well chambered
coverglasses (Nunc, Naperville, IL) at a density of 6000 cells/cm2.
After 48 hours, cells were transfected with 0.85 µg pEYFPER vector DNA,
coding for an ER-targeted enhanced yellow fluorescent protein (EYFP) (Clontech
Laboratories, Palo Alto, CA) and 3.4 µl of FugeneTM transfection
reagent (Roche Diagnostics, Mannheim, Germany).
Antibodies
Immunolocalization of IP3R1 was performed with the previously
characterized antibodies Rbt03 and Rbt04 directed against the C-terminus of
IP3R1 (Parys et al.,
1995), as well as with the antiloopI17a-2 antibody against the
luminal Ca2+-binding site (Maes
et al., 2001
), the anti-cytI3b-1 antibody against the
Ca2+-binding domain 3b localized in the IP3-binding
domain (Sipma et al., 1999
),
and an affinity-purified antibody directed against amino acids 1829-1848
(Affinity BioReagents, Golden, CO).
IP3R3 was localized with the monoclonal antibody MMAtype 3,
obtained from Transduction Laboratories (Lexington, KY), that recognizes the
N-terminal region of IP3R3 (De
Smedt et al., 1997).
Protein disulfide isomerase (PDI) and BiP were visualized with monoclonal
antibodies raised against purified rat PDI (Affinity BioReagents, Golden, CO)
and the C-terminus of human BiP (Transduction Laboratories, Lexington, KY),
respectively. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) was
localized using the AS809-27 polyclonal antibody directed against amino acids
809-827 of SERCA1a that recognizes all SERCA isoforms
(Møller et al.,
1997).
The anti--tubulin monoclonal antibody (Sigma), raised against an
epitope located in the C-terminal end of
-tubulin, was used to detect
the microtubular network. Fluorescein isothiocyanate (FITC)-conjugated
secondary goat anti-mouse and goat anti-rabbit antibodies were from Sigma.
Immunofluorescence of IP3R1 and IP3R3
For confocal microscopy, A7r5 cells were seeded at a density of 8000
cells/cm2 in two-well chambered coverglasses. Stimulation with the
various reagents occurred at 37°C in Ca2+- and
Mg2+-free Dulbecco's phosphate-buffered saline (PBS) for the times
indicated in the legends of the figures, unless otherwise indicated. Control
cells were incubated accordingly in PBS. After incubation, cells were fixed in
3% paraformaldehyde in PBS for 15 minutes at room temperature. After
permeabilization with 0.5% Triton X-100 in PBS for 5 minutes, cells were
washed three times in PBS. Non-specific binding sites were blocked with 20%
goat serum in PBS for 1 hour before incubation with the primary antibodies,
which were diluted in PBS containing 1.5% goat serum. Subsequently, cells were
washed three times with PBS and incubated with the FITC-conjugated anti-rabbit
or anti-mouse secondary antibody. As a control, cells were treated as above
but incubated with either the pre-immune serum of Rbt03 or with PBS before
secondary antibodies were added. The coverglasses were examined using a Zeiss
confocal laser scanning microscope LSM 510 (CLSM) (Carl Zeiss, Jena, Germany)
with a Plan-Neofluar® 40x numerical aperture 1.3 oil-immersion
objective. FITC was excited at 488 nm using an argon laser and fluorescent
light was collected by a photomultiplier after passage through a 505 nm LP
filter. For statistical analysis, random fields were chosen and cells were
counted. A minimum of 100 cells was counted in each independent experiment.
Depending on the localization of IP3R1, two cell types were
discerned: (a) cells with IP3R1 in a preferentially perinuclear
localization, and (b) cells with a homogeneous distribution of
IP3R1. When cells could not clearly be assigned to one of these two
categories, they were classified into a third group, which is referred to as
the intermediate state. The intermediate cell type always amounted to less
than 11% of the total number of cells.
When indicated, 18 slices throughout the entire cell, with an interval of 0.5 µm between each slice, were used to generate a Z-stack. Each of the images of the Z-stack was superimposed over the previous one to generate a flattened Z-stack.
Visualization of ER and cytoskeleton
For immunolocalization experiments, cells were treated as above, using
anti-BiP (1/500), anti-PDI (1/100) and AS809-27 (1/300) for the detection of
the various ER proteins. The ER was also visualized after heterologous
expression of ER-targeted EYFP. Coverglasses containing transfected cells were
investigated 18 hours after transfection with the Zeiss CLSM equipped with a
Plan-Neofluar® 100x, numerical aperture 1.3 oil-immersion objective.
The microtubular network was visualized using the monoclonal antibody
against -tubulin (1/2000) as the primary antibody. As a control, cells
were treated as above but incubated with PBS before the secondary antibody was
added. Since preservation of the microtubular structure may be dependent on
the fixation procedure, we also analyzed microtubuli after fixation in
methanol (-20°C, 3 minutes). Finally, actin was visualized using
rhodamine-phalloidin (1 unit/ml).
Statistics
Data are represented as means±s.e.m. and considered significantly
different when P<0.05 by use of Student's unpaired
t-test. "n" represents the number of independent
experiments.
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Results and Discussion |
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|
Redistribution of IP3R1 after prolonged AVP
stimulation
It has already been shown that in neutrophils, cellular activation can
affect the localization of the intracellular Ca2+ stores
(Stendahl et al., 1994).
Furthermore, short-term agonist stimulation can also lead to clustering of
IP3Rs (Wilson et al.,
1998
). Here we investigated the role of long-term agonist
stimulation on the localization of IP3Rs in A7r5 cells. After
prolonged stimulation of the cells (5 hours) with a supramaximal concentration
of AVP (3 µM) and in the absence of extracellular Ca2+, a
dramatic change was observed in the intracellular localization of
IP3R1. A redistribution of IP3R1 from the perinuclear
region to a more uniform cytoplasmic distribution occurred
(Fig. 1D,E), while no changes
in the localization of IP3R3 could be seen
(Fig. 1F). Since the
redistribution was also observed after the separate confocal images of the
Z-stack were superimposed (Fig.
1D), it represents an overall change in localization. Background
fluorescence was negligible for both isoforms as shown in
Fig. 1G,H.
To quantify the level of redistribution of IP3R1, we assessed the number of A7r5 cells with the IP3R1 predominantly localized in the perinuclear region, or homogeneously distributed in the cytoplasm. When comparing control cells with cells pretreated for 5 hours with AVP (3 µM), the percentage of cells with a perinuclear IP3R1 localization decreased from 74.3±3.2% (n=3) in control cells to 21.3±1.3% (n=3) in AVP-stimulated cells. Simultaneously, the percentage of cells with a cytoplasmic IP3R1 distribution increased from 15.0±3.6% (n=3) in control cells to 72.7±2.3% (n=3) in AVP-stimulated cells. The number of cells in an intermediate state was similar in control cells and in cells stimulated with AVP (10.7±1.2% [n=3] and 6.0±2.5% [n=3], respectively). Identical observations were made in the presence of extracellular Ca2+ (1 mM), although the fluorescence signal was weaker, probably because of enhanced degradation of the IP3Rs (data not shown). The redistribution of IP3R1 was observed with Rbt03, as well as with other antibodies directed against the N- or the C-terminal part of IP3R1, excluding the possibility that the redistribution process only affected a fragment of IP3R1.
Because prolonged stimulation of cells is known to downregulate
IP3Rs (Wojcikiewicz et al.,
1994) via the ubiquitin-proteasome pathway
(Oberdorf et al., 1999
), we
also investigated the redistribution of IP3Rs in the presence of
the proteasome inhibitor MG-132. When added alone MG-132 (20 µM) affected
the localization of IP3R1 (only 49.5±0.5% [n=2] of
the MG-132-treated cells had a perinuclear IP3R1 localization). The
AVP-induced redistribution, however, occurred to the same extent in the
presence or absence of MG-132 (26.3±1.9% [n=3] of cells with a
perinuclear localization).
Time dependence of IP3R1 redistribution
To investigate the time course of the redistribution, we visualized
IP3R1 in cells incubated with AVP for various times.
Fig. 2 shows the percentage of
cells with a perinuclear or a homogeneous distribution of IP3R1 as
a function of time of incubation with AVP (3 µM). Interestingly, during the
first hour, IP3R1 remained localized in the perinuclear region. The
redistribution occurred mainly during the second hour after AVP addition,
after which it stabilized. We examined whether this process was reversible by
removing AVP after 2 hours. Within one hour, there was a nearly full recovery
of the original perinuclear distribution (dotted line in
Fig. 2), indicating that cells
suffered no irreversible damage. Identical results were obtained in the
presence or absence of extracellular Ca2+. These results provide
further evidence that the redistribution occurs independently of
downregulation, since downregulation was shown to be much slower and more
gradual (Sipma et al., 1998).
Moreover, downregulation is an irreversible process
(Oberdorf et al., 1999
),
whereas the redistribution was fully reversible.
|
IP3R1 redistribution can be induced by
Ca2+-releasing agents
In A7r5 cells, AVP stimulates a single class of vasopressin receptors
(V1A) leading to the activation of PLC, phospholipase D and
phospholipase A2. We used the PLC activator imipramine
(Fukuda et al., 1994) to
examine whether the inositol lipid signaling pathway was involved in
IP3R1 redistribution. Imipramine (50 µM) added to the cells for
4 hours was able to induce the redistribution as effectively as AVP (3 µM)
for the same time period (with imipramine 20.0±7.0% [n=2] and
with AVP 26.3±1.2% [n=3] of cells with IP3R1
located in the perinuclear region) indicating that the inositol lipid
signaling pathway is involved. Since PLC activation leads to the production of
IP3 and DAG, we investigated the role of each of these second
messengers. Raising only the intracellular IP3 concentration by
using a cell permeable IP3 ester (IP3BM)
(Thomas et al., 2000
) induced
the redistribution of IP3R1 (data not shown). Furthermore,
increasing the free cytoplasmic Ca2+ concentration by emptying the
stores using the SERCA pump inhibitors thapsigargin and CPA also led to an
identical redistribution of IP3R1
(Fig. 3).
|
PKC is involved in the redistribution of IP3R1
A common downstream target of DAG and Ca2+ is PKC. We therefore
determined whether PKC could play a role in the redistribution of
IP3R1. Activation of PKC with 50 µM of the diacylglycerol analog
OAG for 5 hours caused the redistribution of IP3R1 to the
cytoplasm, which was nearly as prominent as that obtained with AVP
(Table 1). This result was
verified by the use of different PKC inhibitors
(Table 1). Staurosporine (200
nM), a broad-spectrum inhibitor of protein kinases, inhibited both the AVP-
and thapsigargin-induced redistribution. When added alone, it had no effect on
the IP3R1 localization. Staurosporine, however, did not change the
cytoplasmic localization of IP3R3, showing that the observed
inhibition was not due to a general collapse of the ER structure around the
nucleus (data not shown). The more selective PKC inhibitor bisindolylmaleimide
I hydrochloride (100 nM) added to the cells together with AVP induced only a
partial inhibition of the redistribution of IP3R1, whereas the
inhibitor itself had no effect on the intracellular localization of
IP3R1. Gö-6976, a specific inhibitor of the PKC and
PKCß isoforms, also had no effect on the localization of IP3R1
itself, but again partially inhibited the redistribution when added to the
cells together with AVP. The partial inhibition of the redistribution by
bisindolylmaleimide I hydrochloride and Gö-6976 may be explained by the
fact that these compounds differently inhibit the various PKC isoforms. In
A7r5 cells, three isoforms of PKC are activated upon stimulation with AVP,
namely
,
and
(Fan and
Byron, 2000
). Staurosporine (200 nM) inhibits the
,
ßI, ßII,
,
and
isoforms,
bisindolylmaleimide I hydrochloride the
, ßI,
and
isoform and Gö-6976 inhibits the
and
ßI isoforms. Taking the effects of the various PKC inhibitors
into account, our findings therefore strongly suggest a role for at least
PKC
in the redistribution process.
|
Role of the microtubular network in IP3R1
redistribution
Since PKC has been shown to modulate the cytoskeleton
(Keenan and Kelleher, 1998),
which has an important function in vesicle trafficking processes, we
investigated whether microfilaments or microtubules were involved in
IP3R1 redistribution. Actin was visualized using
rhodamine-phalloidin. In resting cells, the actin microfilaments appeared as
stress fibers dispersed over the whole cell
(Fig. 4B). Stimulation for 5
hours with AVP or OAG did not lead to significant structural changes
(Fig. 4D,F).
|
Microtubules were visualized using an antibody directed against
-tubulin. In unstimulated A7r5 cells, the microtubular network
consisted of short tubules, which were predominantly found around the nucleus,
and long tubules located under the plasma membrane as can be seen in
Fig. 4A. After 5 hours of
stimulation with AVP (3 µM), the microtubules had spread out over the
entire cytoplasm (Fig. 4C).
Identical results were obtained when PKC was activated with OAG for 5 hours
(Fig. 4E). Visualizing the
microtubules after fixation with methanol gave similar results (data not
shown), although quantitatively some differences were observed. In particular,
although in paraformaldehyde-treated cells about 80% of the cells were
characterized by a tubular network concentrated around the nucleus, such a
pattern was only detected unambiguously in about 30% of the cells after
methanol fixation. This pattern was, however, seldom found after AVP or OAG
treatment, and this was independent of the fixation technique. PKC has already
been shown to affect the microtubules. In neuronal growth cones, activation of
PKC increased the growth lifetime of the microtubules, thereby promoting the
extension of the distal microtubules from the central domain into the
F-actin-rich peripheral domain where they are normally excluded
(Kabir et al., 2001
).
To further investigate the potential role of the microtubules in the redistribution process, we used the microtubule-disrupting agent nocodazole and the microtubule-stabilizing agent taxol. Fig. 5 shows the number of cells that contained a perinuclear IP3R1 distribution after 2 hours of stimulation with AVP (3 µM) in the absence or presence of nocodazole (50 µM) or taxol (1 µM). The results show that both nocodazole and taxol could completely inhibit the AVP-induced redistribution, while each agent itself had no effect on the perinuclear localization of IP3R1 (Fig. 5). Interestingly, neither compound affected the localization of IP3R3 (data not shown). Taken together, these results clearly indicate an important role for the microtubular network in IP3R1 redistribution.
|
Specific ER proteins redistribute after AVP stimulation
ER structure is known to be susceptible to changes in physiological
situations such as oocyte maturation
(Terasaki et al., 2001) or
after prolonged increases in cytosolic Ca2+ concentration
(Subramanian and Meyer, 1997
).
In addition, it was shown that PKC could protect the structure of the ER from
the effects of abnormally high cytosolic Ca2+ concentrations
(Ribeiro et al., 2000
). Since
the IP3R is mainly an ER-residing protein, we first verified
whether the gross morphology of the ER was modified after agonist stimulation.
To visualize the ER structure, cells were transfected with the pEYFP-ER
vector, which encodes an ER-targeted yellow fluorescent fusion protein. The
effect of prolonged incubation with AVP on ER structure was examined 18 hours
after transfection. Confocal images of paraformaldehyde-fixed cells were
obtained from control cells and from cells treated with AVP (3 µM) for 5
hours. Fig. 6A shows a
representative control cell. The ER appeared as an intricate network of
tubules and vesicular structures expanding from the nuclear envelope to the
periphery of the cell. Incubation of cells for 5 hours with AVP did not lead
to significant changes in ER morphology
(Fig. 6B). To avoid possible
fixation artifacts, identical experiments were performed on intact cells, with
similar results (data not shown).
|
Furthermore, we investigated whether typical ER-residing proteins displayed a similar behavior as IP3R1. PDI was homogeneously distributed over the entire cell, both in unstimulated and AVP-stimulated cells (Fig. 6C,D). Staining patterns for the chaperone protein BiP were identical to those of PDI and are consistent with ER structure staining (data not shown).
Finally, we investigated the localization of the SERCA-type Ca2+
pumps. These pumps are important for the filling of the Ca2+
stores, and are thought to functionally co-localize with the Ca2+
release channels (Favre et al.,
1996). Interestingly, in unstimulated cells SERCA distribution was
similar to IP3R1 distribution, i.e. predominantly found in the
perinuclear region, although to a lesser extent (51.0±1.2%
[n=3] of cells with perinuclear SERCA compared with 74.3±3.2%
[n=3] of cells with perinuclear IP3R1)
(Fig. 7A). In addition,
isolated peripheral patches were also found for SERCA. After stimulation with
AVP (3 µM) for 2 hours, a redistribution of SERCA occurred from the
perinuclear region to a more homogeneous distribution over the entire cell
(33.0±1.0% [n=3] of cells with a perinuclear SERCA)
(Fig. 7B). These results
indicate that although the general ER structure is not affected, specific
proteins involved in Ca2+ signaling processes, such as
IP3R1 and SERCA, are redistributed after prolonged agonist
stimulation.
|
Potential role of vesicle trafficking in IP3R1
redistribution
Although the ER can be considered as one continuous membrane compartment,
the subcellular localization of intracellular Ca2+ release channels
located to the ER may not be uniform
(Petersen et al., 2001). In
A7r5 cells, it has been shown that the perinuclear region functionally
contained the highest density of Ca2+ stores
(Blatter, 1995
). In resting
A7r5 cells, IP3R1 is precisely concentrated in that region. In some
cell types, it was shown that IP3R1 localization could be
restricted by its interaction with scaffolding proteins such as homer
(Tu et al., 1998
;
Salanova et al., 2002
) or
ankyrin-B (Mohler et al.,
2002
). A restricted localization by interaction with cytoskeletal
proteins could also be responsible for IP3R1 localized at the cell
periphery (Sugiyama et al.,
2000
). Prolonged cellular activation might modulate these
interactions and could result in the unrestricted movement of IP3Rs
within the structure of the ER. Results obtained thus far, however, do not
point to a significant role of homer or ankyrin in IP3R
distribution in A7r5 cells (E. Venmans, E.V., H.D.S. and J.B.P.,
unpublished).
Another possibility is that IP3R1 is located in the perinuclear region and redistributes to the ER through vesicle trafficking. To investigate this hypothesis we first verified whether brefeldin A could affect IP3R1 localization. Brefeldin A (2 µg/ml) treatment for 2 hours induced a complete redistribution of IP3R1 (after treatment: 29.3±1.7% [n=4] cells with a predominant perinuclear localization), suggesting that vesicle trafficking might be involved.
Because the perinuclear immunostainings of IP3R1 in resting
cells are suggestive of IP3R1 being localized in the
vesiculotubular clusters of the intermediate compartment, we incubated cells
for 2 hours at 15°C. At this temperature, the vesicular transport of
proteins is blocked at the level of the intermediate compartment
(Saraste and Kuismanen, 1984).
Such treatment had no effect on the localization of the IP3R1
(71.3±3.5% [n=3] of cells with a perinuclear localization of
IP3R1) but completely inhibited its AVP-induced redistribution
(after treatment 75.7±2.6% [n=3] of cells with a perinuclear
localization of IP3R1). Similar results were obtained when
thapsigargin was applied to induce the redistribution.
These results strongly suggest a role for vesicle trafficking in the
redistribution process. Moreover, our results concerning the AVP-induced
redistribution of the SERCA pumps are in good agreement with this hypothesis.
Indeed, it might be expected that IP3R1 and SERCA redistribution
are related. Although both Ca2+ transport proteins functionally
co-localize (Favre et al.,
1996), there is no evidence for either a direct or an indirect
structural interaction between both. Finally, the results obtained in the
presence of nocodazole or taxol indicate that the microtubular network, which
is known to play an important role in vesicular trafficking, is likely to be
involved in the redistribution. These results are in agreement with recent
results describing that the redistribution of the Ca2+ stores in
newt eggs also required the microtubular network
(Mitsuyama and Sawai, 2001
).
Moreover, PKC that also activates IP3R1 redistribution is related
to microtubular outgrowth (Kabir et al.,
2001
) and to ER organization after excessive Ca2+
release (Ribeiro et al.,
2000
).
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Conclusion |
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Acknowledgments |
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References |
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