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Department of Surgery, Division of Trauma, New Jersey Medical School, Newark, NJ 07103
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When agonists bind to the receptors, inositol 1,4,5-triphosphate (InsP3) interaction with its receptors in the endoplasmic reticulum (ER) results in rapid Ca2+ release from ER stores. Such calcium store release depletes ER Ca2+ stores and subsequently activates Ca2+ influx across the plasma membrane by mechanisms generally referred to as store-operated (or capacitative) calcium entry (SOCE) (2). Our clinical experience (3) suggested that PMN dysregulation due to injury and inflammation involved abnormally enhanced SOCE, and other authors have demonstrated that SOCE is required for the activation of PMN functions seen in inflammatory surroundings (4, 5, 6).
However, the exact mechanisms of SOCE continue to be a subject of great controversy (7). Visual phototransduction in Drosophila uses a G protein-coupled receptor mechanism linked to SOCE. After cloning of the Drosophila transient receptor potential gene (trp), in vitro expression studies indicated that TRP was a cationic influx channel activated by Ca2+ signaling from cell stores (8, 9). Multiple isoforms of trp have subsequently been cloned based on data from Drosophila, and recent work has implicated calcium channel proteins of the TRP superfamily in the mediation of human SOCE (10, 11, 12, 13, 14, 15, 16).
Thus, the human genome is known to contain many candidate SOCE channel proteins. Consequently, cells may express them individually or in combination (16), and such expression profiles may play a role in achieving phenotype-specific calcium entry responses. However, no studies exist evaluating whether SOCE in human cells is a unitary process or reflects the summated contributions of combined calcium entry pathways. Therefore, we examined the hypothesis that net PMN SOCE after inflammatory stimulation might reflect the contribution of multiple pathways, rather than a single calcium entry pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Freshly withdrawn healthy human blood was used to prepare PMN samples. A detailed protocol is described elsewhere (17). Briefly, heparinized whole blood (10 U/ml) was centrifuged at 150 x g for 10 min. The plasma and platelets were discarded. The buffy coat and RBC were layered onto Polymorphoprep (Robbins Scientific, Sunnyvale, CA), followed by a 30-min centrifugation at 300 x g. The PMN layer was collected and diluted with an equal volume of 0.45% NaCl to restore osmolarity. The suspensions were then washed in RPMI 1640 and centrifuged at 150 x g for 10 min. Neutrophil pellets were suspended in 2 ml HEPES buffer (20 mM HEPES, 140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM glucose, and 0.1% BSA, pH 7.4). PMN were counted on a flow cytometer and kept on ice until dye-loaded for study.
Dye loading and preincubation
PMN were incubated in 1 µM fura 2-AM (Molecular Probes, Eugene, OR) at 37°C for 30 min in the dark. Specimens were divided into aliquots of 2 x 106 cells and placed on ice in the dark until ready for use. Just before each experiment, individual aliquots were incubated at 37°C for 5 min. Cells were then pelleted by centrifugation at 4500 rpm for 5 s in a programmable microcentrifuge and resuspended in 3 ml HEPES in the cuvette. Experiments were generally begun in nominally calcium-free medium containing 0.3 mM EGTA. The sole exceptions were the experiments involving cationic inhibitors (Gd3+, La3+, etc.). These were performed in calcium-free medium without EGTA to avoid chelation of the inhibitors.
Divalent cation measurements by spectrofluorometry
Intracellular calcium was monitored by measuring fura fluorescence at 505 nm, using 340/380-nm dual wavelength excitation in a Fluoromax-2 spectrofluorometer (Jobin Yvon-Spex, Edison, NJ). Cuvette temperatures were kept at 37°C with constant stirring. Calibration was performed at the end of each experiment by the addition of 100 µM digitonin (Molecular Probes) for RMAX and then 15 mM EGTA for RMIN. The autofluorescence of a sample cell suspension treated with 100 µM digitonin and 2 µM MnCl2 was subtracted from total fluorescence. The [Ca2+]i was then calculated from the 340:380-nm fluorescence ratio (Kd = 220 nM) as per the methods of Grynkiewicz et al. (18). Dye leakage is trivial and has no influence on [Ca2+]i calculations using our methods. The order of study of isolates was alternated to avoid bias related to duration of dye loading or time of cell study.
Modifications of these methods were used to assess the apparent influx
of strontium ions
([Sr2+]i).
Sr2+ has a lesser affinity for fura than does
Ca2+, and its binding causes less fluorescence,
but its isobestic point and 340:380 ratio profile are very similar
(19). However, we noted in preliminary studies that
[Ca2+]i store release
measurements were unaffected by the presence of
Sr2+ in the medium at the time of cell lysis for
calibration of RMAX and
RMIN (Fig. 1
A). Thus, we found we could
quantitatively assess Ca2+ store release and
qualitatively assess relative Sr2+ and
Ca2+ entry into PMN in the same experiments by
serial addition of Sr2+ (to 1 mM) and then
Ca2+ (to 1 mM) to the medium after resolution of
the store release transients. As seen in Fig. 1B, this
method allows us to assess the area under the curve (AUC) for
Ca2+ release in
Ca2+/Sr2+-free medium, as
well as the relative magnitude of Sr2+ and
Ca2+ entry as those ions are added to the medium
(see below). Thus, initial
[Ca2+]i traces from
experiments in which Sr2+ is added later are both
quantitatively and qualitatively correct. However, because of its
higher Kd for fura and the potential
for interactions, [Sr2+]i
is always reported as apparent
[Sr2+]i. Similarly,
[Ca2+]i measurements made
after addition of Sr2+ may be inexact, and are
therefore treated as apparent. However, in all cases only experimental
responses obtained under identical conditions are compared.
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Cytosolic [Ca2+]i
responses, apparent
[Ca2+]i responses after
Sr2+ influx, and apparent
[Sr2+]i responses were
measured and recorded both as the peak
[Ca2+]i response
(measured in nanomoles) and as the integrated AUC (measured in
nanomoles x seconds) for the 100 s after stimulation with
the agonist in question, or in arbitrary units of concentration x
seconds after the addition of external
Sr2+ or Ca2+. Both the peak
influx and the duration of influx signals may be of importance in
determining specific cell responses to calcium. We elected to combine
these parameters by assessing the AUC. This pharmacologic approach
creates a quantitative and reproducible assessment of total influx. AUC
measurements diminish the effect of artifacts on assessments while
avoiding the use of curve-smoothing programs. The AUC does not address
differences in peak and duration of response individually. These may
have considerable physiologic significance, but no changes in the
morphology of SOCE currents were seen in these studies to suggest that
peak and duration of influx changed independently under the conditions
used. Integration of concentration curves (Fig. 1
B) was performed using an
automated software package (GRAMS/32; Galactic Industries, Salem, NH).
Data analysis was done using SigmaPlot and SigmaStat software (SASS,
Chicago, IL).
Where mathematical curve fitting was performed to assess the
relationships between store release and Sr2+ or
Ca2+ influx, each curve-fit analysis was
performed using two different software packages (SigmaStat and 2-D
Curve-fit; SPSS, Chicago, IL). The function with the highest
R value was accepted as most representative of the form of
the relationship. A p value 
0.01 was required before
accepting that a curve fit was indicative of a significant
relationship.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Prior studies have shown that cells transfected with TRP3 had
enhanced permeability to strontium ions (Sr2+)
after store depletion (20). Others, however, have
suggested that SOCE occurs through channels that are calcium selective
(1). We examined this question by stimulating PMN with 100
nM fMLP. Addition of Sr2+ (1 mM) to the medium
after resolution of the store depletion transient resulted in a brisk
influx event. Nonetheless, subsequent addition of
Ca2+ (1 mM) resulted in a further influx event
(Fig. 2A). This influx was Ca2+
specific, because Sr2+ influx was saturated at 1
mM and showed no further entry at higher concentrations (Fig. 2C). Direct addition of 1 mM Ca2+ to
the medium after store depletion yields an influx response (Fig. 2B) similar to that seen when Ca2+ was
applied after Sr2+. In the presence of
extracellular Ca2+, neither
Sr2+ (Fig. 2B) nor further
Ca2+ (to 2 mM) increased apparent
[Ca2+]i (Fig. 2D).
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, A
and B). Dependence of Sr2+ and Ca2+ entry on store release
Our initial results suggested that PMN calcium entry integrates
multiple SOCE pathways, which show differential cation permeability.
Because influx in these studies was initiated by a G protein-coupled
mediator (fMLP), an argument could be made that some portion of the
cation entry seen might have occurred through receptor-operated
mechanisms. We therefore studied whether store emptying per se elicited
similar patterns of Sr2+ and
Ca2+ entry in the PMN. To do this, we stimulated
PMN with ionomycin at very low doses (100 nM). This depletes calcium
stores, and allows study of subsequent Sr2+ and
Ca2+ entry. In addition, it has been suggested
that the opening of some store-operated calcium channels by store
depletion requires a physical coupling between
InsP3 receptors and the channels themselves
(21). Therefore, we used the same system to evaluate
whether blockade of the InsP3 receptors (using
2-aminoethyoxydiphenyl borane (2-APB)) would differentially affect
ionomycin-induced store-operated PMN Ca2+ and
Sr2+ entry. We found that isolated store
depletion by ionomycin led to responses very similar to those elicited
by fMLP in that Ca2+ still enters the PMN after
store-operated Sr2+ entry is complete (Fig. 3, upper line). However, we
found that Sr2+ entry was almost totally
inhibited by 2-APB, whereas Ca2+ entry was
relatively unaffected (Fig. 3, lower line). These data
further support the concept that calcium store depletion activates two
different divalent cation entry pathways in PMN. The
Sr2+-permeable mechanism is 2-APB inhibitable.
The second, more Ca2+-specific pathway allows
greater Ca2+ influx and is relatively 2-APB
resistant.
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One of the accepted characteristics of SOCE is that it is
inhibited by gadolinium (Gd3+) at low
concentrations (22). Therefore, we studied the inhibitory
effects of Gd3+ on PMN Ca2+
and Sr2+ entry after both G protein-coupled
chemoattractant store depletion (using fMLP) and direct store depletion
using the Ca2+-ATPase inhibitor thapsigargin
(TG). We found that Gd3+ inhibited
Sr2+ entry at far lower concentrations than it
inhibited Ca2+ entry. This was true for both G
protein-coupled and direct store depletion-initiated cation entry. PMN
Sr2+ and Ca2+ entry at
Gd3+ concentrations from 1 nM to 10 µM was then
assessed and curve fit over its linear range (Fig. 4). The EC50 of
Gd3+ for inhibition of Sr2+
entry was 48 nM for fMLP-mediated entry and 81 nM for TG-mediated
entry. In contrast, the EC50 of
Gd3+ for inhibition of Ca2+
entry was 2291 nM for fMLP-mediated entry and 1019 nM for
TG-mediated entry. Thus, after both types of store depletion, G protein
mediator dependent and direct store depletion dependent,
Gd3+ was 10- to 20-fold more potent as an
inhibitor of Sr2+ than of
Ca2+ entry. However, in all cases the inhibitory
Gd3+ concentrations were well within those
generally used to inhibit SOCE (22). Interestingly, the
inhibition of Sr2+ entry by
Gd3+ found in this study was very similar to that
found in studies of TRP3 by Halaszovich (23). Moreover,
TRP3 channels are known to allow nonselective
Sr2+ entry (15).
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These inhibitor studies support the concept that PMN Ca2+ entry in response to G protein-coupled chemoattractants occurs through the same pathways as those activated by direct store depletion, and thus that they are truly store operated. Moreover, the detailed studies of inhibition of Sr2+ and Ca2+ entry by Gd3+ support the concept that at least two store-operated entry pathways exist in PMN. The nonselective, Sr2+-permeable pathway is inhibited Gd3+ at low (<100) nM concentrations. Ca2+-specific entry is inhibited by Gd3+ at 10- to 20-fold higher concentrations (1–2 µM).
Sr2+ and Ca2+ entry are differentially store-depletion dependent
Having determined that both Sr2+ and
Ca2+ entry could be elicited by store depletion,
we assessed their dependence upon the degree of store depletion. PMN
were exposed to TG for varying lengths of time in divalent cation-free
medium (Fig. 5) and then exposed either
to 1 mM Sr2+, or to 1 mM
Ca2+ in the presence of 500 nM
Gd3+ (thus blocking all influx through
Sr2+-permeable pathways). Because TG depletes ER
calcium stores passively by blocking reuptake, depletion is progressive
over time. We noted that both the rate of rise and the maximal extent
of Sr2+ influx became maximal early in the course
of store depletion. Both the rate of rise and the maximal extent of
entry through the calcium-specific pathway were more dependent upon the
completeness of store emptying, taking over three times as long to
achieve maximal influx. Again, these findings demonstrate marked
differences in cation influx through the two mechanisms: the
nonspecific Sr2+-permeable pathways appear to
allow brisk early responses that are relatively independent of the
degree of store depletion; the Ca2+-specific
influx mechanism is more regulated by the degree of store depletion,
and may allow for later entry of larger amounts of calcium.
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In vivo, PMN SOCE may occur when calcium stores are mobilized by a
wide variety of G protein-coupled chemoattractants. We hypothesized
that PMN stimulation at specific G protein-coupled receptors might
elicit unique SOCE responses. We therefore compared
Sr2+ and Ca2+ entry
responses with Ca2+ store depletion elicited by
three different G protein-coupled chemoattractants. Each of these is
physiologically important in human PMN function, but elicits different
PMN functions as well as unique
[Ca2+]i transient
morphology (3). Platelet-activating factor (PAF) is a
lipid autocoid crucial to many inflammatory processes. PMN calcium
entry after PAF stimulation occurs exclusively via SOCE
(17). fMLP activates PMN via receptors for formylated
(bacterial) peptides. IL-8 is a chemokine with important roles in PMN
chemotaxis and priming. IL-8 acts via two receptors (CXCR1 and CXCR2).
In these studies, therefore, we blocked CXCR2 with a specific mAb (gift
of J. Bussiere, Genentech, South San Francisco, CA) to isolate the
actions of IL-8 at CXCR1. In each of these studies, PMN were exposed to
ascending agonist doses from zero to the EC100
for [Ca2+]i store
depletion in calcium-free medium. Each point in Figs. 6A,
7A, and
8A represents the mean ±
SE of 6–10 experiments. As expected, PMN Ca2+
store release increases in a dose-dependent fashion when PMN are
stimulated by each of the agonists tested. However, store-operated
Sr2+ and Ca2+ entry
responded in different and quite unique ways after each specific
agonist.
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A). Each was maximal after 1 nM
PAF and none increased at higher agonist doses. In contrast, when PMN
were treated with fMLP (Fig. 7A), store release always
exceeded Ca2+ entry, which always exceeded
Sr2+ entry. Moreover, even though store release
was maximal at all fMLP concentrations 
1 nM,
Sr2+ and Ca2+ entry
responses continued to increase with increasing fMLP concentration.
IL-8 stimulation of CXCR1 (Fig. 8A) resulted in significant
store release at doses 10 nM. However, Sr2+ and
Ca2+ entry after IL-8 were never greater than the
nonspecific Sr2+ and Ca2+
entry (leak current) that is seen when nonstimulated PMN in
calcium-free medium are exposed to Ca2+ or
Sr2+. Thus, after IL-8, no
Sr2+ or Ca2+ entry was seen
even at levels of receptor activation and store release that were
associated with brisk Sr2+ and
Ca2+ entry after PAF or fMLP.
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To further analyze these relationships, we curve-fit the store release
Sr2+ and Ca2+ entry data
for each agonist. Highly linear relationships were noted
(R > 0.99 and p < 0.001) between
store release and both Sr2+ and
Ca2+ entry after PAF exposure (Fig. 6B). Thus, after PAF, both Sr2+ and
Ca2+ influx appear to be direct linear functions
of store release. This suggests that calcium store release is the major
determinant of both nonspecific and Ca2+-specific
divalent cation entry after PAF stimulation. In contrast, fMLP
stimulation (Fig. 7B) yields an exponential relationship
(R > 0.82 and p < 0.001) between
store release and divalent cation entry. Both nonspecific and
Ca2+-specific divalent cation entry became less
dependent upon store depletion and more dependent on agonist
concentration at increasing fMLP concentrations. Thus, after fMLP,
store release leads to SOCE, but this SOCE is modulated by other
secondary mechanisms. No significant cation entry was seen after IL-8
stimulation. Thus, no meaningful mathematic relationship could be found
between store release and cation entry under these conditions
(R < 0.10 and p > 0.5 for all
equations tested; Fig. 8B).
Thus, the mechanisms linking store release and calcium entry vary markedly with the specific G protein-coupled receptor activated. Furthermore, it appears that although calcium entry into the PMN may be initiated by store depletion, it can be quantitatively regulated by other factors that are determined by the initiating G protein complex as well as by the degree of store depletion. Moreover, the initiating G protein receptor complex appears to regulate the relationships between store release and divalent cation entry both through the Sr2+-permeable and the Ca2+-selective PMN calcium entry pathways in ways that are roughly parallel.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present data confirm that PMN SOCE responses to clinically relevant agonists occur through multiple pathways. The prolongation of elevated [Ca2+]i levels in PMN after G protein-coupled receptor stimulation represents the summation of at least two such contributions. These pathways fulfill the usual definitions of SOCE both in that they are activated by passive store depletion and by virtue of their ionic inhibitor profiles. Yet the two pathways differ in the magnitude and time course of their contributions to calcium flux, the EC50 of inhibition by Gd3+, and their inhibition by the InsP3 receptor inhibitor 2-APB. Most importantly, though, these influx pathways demonstrate differential regulation when activated by different G protein-coupled receptor agonists, thus suggesting an entirely novel mechanism by which [Ca2+]i and downstream cellular function can be regulated in nonexcitable cells.
The contributions of TRP channels to SOCE are still controversial, but work in both expression and wild-type systems shows that TRP channels can participate in SOCE (21, 25, 26, 27) as well as respond to G protein signaling complex-generated mediators such as diacylglycerol (28, 29, 30). The divalent cation entry pathways we find in human PMN also appear to have some characteristics usually attributed to receptor operated as well as to SOCE. Similar complexity in the relationships between store-emptying and TRP activation has been noted by others (31). Parekh et al. (32) found that ICRAC currents were nonlinearly activated in RBL cells by G protein-coupled muscarinic receptors. We noted exponentially increasing activation of Ca2+ influx at high doses of fMLP. In contrast, PAF mobilized cation influx linearly over a broad range of store release. IL-8 acting at CXCR1 failed to elicit SOCE. This might reflect a failure to achieve a trigger concentration of InsP3 and store release. Conversely though, because high doses of IL-8 do achieve store release equivalent to mid-dose PAF, this could imply the generation of a secondary SOCE-suppressive event by CXCR1 stimulation.
Such complexity has also been hypothesized to suggest the possible formation of heteromultimeric TRP channels (30, 33). Based upon their primary sequences, TRP proteins are predicted to have six transmembrane segments similar to those found in voltage-dependent Ca2+, Na+, and K+ channels (34). Because such Na+ and Ca2+ channel proteins form pores using four repeated six-transmembrane domains, it is probable that TRP channels also function as homo- or heterotetramers of TRP proteins (1, 34). Such heteromultimeric channels could incorporate multiple control mechanisms inherent to each of their component subunits.
In other studies (data not shown), we have noted that four distinct TRP proteins can be found in circulating PMN. If indeed TRP channel proteins do mediate SOCE in PMN, those data would imply that either multiple channel types or heteromultimeric channels must exist. Thus, our findings may also suggest that the control of calcium entry in wild-type nonexcitable cells like PMN may depend on the relative expression of channel proteins and on their assembly into functional channels as well as on the characteristics of the individual channel proteins.
The involvement of multiple component pathways will complicate attempts to understand the role and regulation of SOCE in inflammatory responses. However, such diversity also suggests that the molecular control of SOCE may play a role in conferring stimulus-response specificity to PMN-mediated inflammation as well as to other [Ca2+]i-driven immune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Carl J. Hauser, Department of Surgery, New Jersey Medical School, MSB G-524, 185 South Orange Avenue, Newark, NJ 07103. E-mail address: hausercj{at}umdnj.edu
3 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; 2-APB, 2-aminoethyoxydiphenyl borane; AUC, area under the curve; [Ca2+]i, cytosolic calcium concentration; ER, endoplasmic reticulum; InsP3, inositol 1,4,5-triphosphate; PAF, platelet-activating factor; SOCE, store-operated calcium entry; [Sr2+]i, apparent cytosolic strontium concentration; TG, thapsigargin; TRP, transient receptor potential.
Received for publication October 25, 2001. Accepted for publication February 13, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and SrE (
) are highly correlated to the
magnitude of SR in a linear fashion.
