1 Department of Physiology and Biophysics and 2 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005
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ABSTRACT |
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The coupling mechanism between depletion of Ca2+ stores in the endoplasmic reticulum and plasma membrane store-operated ion channels is fundamental to Ca2+ signaling in many cell types and has yet to be completely elucidated. Using Ca2+ release-activated Ca2+ (CRAC) channels in RBL-2H3 cells as a model system, we have shown that CRAC channels are maintained in the closed state by an inhibitory factor rather than being opened by the inositol 1,4,5-trisphosphate receptor. This inhibitory role can be fulfilled by the Drosophila protein INAD (inactivation-no after potential D). The action of INAD requires Ca2+ and can be reversed by a diffusible Ca2+ influx factor. Thus the coupling between the depletion of Ca2+ stores and the activation of CRAC channels may involve a mammalian homologue of INAD and a low-molecular-weight, diffusible store-depletion signal.
store-operated ion channels; inositol 1,4,5-trisphosphate receptor
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INTRODUCTION |
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AGONIST-RECEPTOR INTERACTIONS at the plasma membrane often lead to the generation of inositol 1,4,5-trisphosphate (IP3), which in turn releases Ca2+ from internal stores in the endoplasmic reticulum (ER). Such depletion of Ca2+ stores gives rise to a signal that activates Ca2+-permeable store-operated channels (SOCs) in the plasma membrane, allowing for the sustained Ca2+ influx termed capacitative or stored-operated Ca2+ entry (6, 36). Four not necessarily distinct models have been proposed to account for the activation mechanism of SOCs (37). First, a physical link between IP3 receptors (IP3R) and SOCs is proposed (15, 17, 22, 35). Changes in the conformation of IP3R upon IP3 binding and/or store depletion activates SOCs. In the second, secretory-like transport vesicles are proposed as a source for the insertion of channels previously not present in the plasma membrane (30, 55). Third, a freely diffusible soluble messenger molecule, termed Ca2+ influx factor (CIF), is formed upon Ca2+ store depletion and activates the SOCs (8, 14, 38, 39, 44, 47), either directly or through interaction with closely associated regulatory proteins. Fourth, SOCs are kept in an inhibited state by an inhibitory mechanism when the Ca2+ stores are full, and discharge of Ca2+ stores removes such an inhibitory mechanism (37).
The Ca2+ release-activated Ca2+ (CRAC) channel is the best characterized of the SOCs (29). Its activation mechanism remains largely unknown (7), although several aspects of this regulation have been established. First, it is clear that depletion of intracellular Ca2+ stores (12, 28) leads to the activation of ICRAC (current conducted by CRAC channels) within tens of seconds. Second, CRAC channels in RBL cells are not likely activated by a secretion-like coupling mechanism (1). Third, CRAC channels in chicken DT40 cells in which all isoforms of IP3R are knocked out are activated normally upon store depletion, suggesting that physical coupling between IP3R and CRAC channels is not a mechanism of CRAC activation (33, 45). Fourth, whole cell patch-clamp experiments have established that achieving this electrophysiological configuration itself leads to ICRAC development, but only after hundreds of seconds and progressively less rapidly as the [Ca2+] in the pipette solution is buffered to levels approaching or exceeding 100 nM (12, 28). Importantly, this activation is seen well before global ER Ca2+ store depletion is observed (19). This finding suggests that low Ca2+ itself is sufficient to activate ICRAC, at least in the context of the large dilution of cytoplasmic constituents resulting from equilibration with the patch pipette solution. One explanation for this result invokes the dissociation of a regulatory factor from the CRAC channel, a dissociation that is facilitated by low levels of Ca2+ and dilution of the cytoplasm. Fifth, we have recently determined (8) that partially purified acid extracts from cells in which Ca2+ stores have been depleted, either with thapsigargin or by genetic disruption of sarcoplasmic endoplasmic reticulum Ca2+ ATPase, will accelerate the activation of ICRAC in whole cell patch-clamp experiments. This provides compelling evidence for the existence of a CIF-like molecule in CRAC channel regulation. However, how CIF might activate CRAC channels is essentially unknown. Here, we begin to reconcile these findings and suggest a unified model for CRAC channel activation.
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MATERIALS AND METHODS |
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Cell culture. Rat basophilic leukemia (RBL-2H3) cells were purchased from the American Type Culture Collection (Rockville, MD) and were maintained at 37°C in 5% CO2 in Eagle's minimum essential medium (Sigma, St. Louis, MO) with the following substitutions (Mediatech, Herndon, VA): 10% heat-inactivated fetal calf serum, 10,000 IU/ml penicillin, 10,000 µg/ml streptomycin, 2 mM glutamine, 10 mM sodium pyruvate, 10 mM nonessential amino acid, and 25 mM HEPES. Cells were treated by trypsin, plated on coverslips, and used on days 3 and 4.
Patch-clamp recordings.
Whole cell recordings were performed with RBL-2H3 cells at room
temperature. Standard external solution contained (in mM) 143 NaCl, 10 CaCl2, 1 MgCl2, 5 D-glucose, 4.5 KCl, 0.5 BaCl2, and 10 HEPES, pH 7.3 adjusted with NaOH.
Ca2+-free solution (CFS) was made by replacing
CaCl2 in this solution with an equimolar concentration of
MgCl2 to abolish ICRAC and to obtain
a leak current for subtraction to eliminate possible contamination
current from Mg2+-inhibited cation (MIC) channels
(34). Divalent cation-free solution (DVF) contained (in
mM) 160 Na-methane sulfonate, 5 D-glucose, 2 Na-EGTA, and
10 HEPES, pH 7.2 adjusted with NaOH. Standard internal solution for
whole cell recordings contained (in mM) 110 Cs-glutamate, 10 CsCl, 2.9 MgCl2, 0.6 CaCl2, 10 Cs-EGTA, and 30 HEPES, pH
7.2 adjusted with CsOH. The calculated free [Ca2+] and
[Mg2+] were 10 nM and 2 mM, respectively. To obtain 100 nM free [Ca2+], the CaCl2 and
MgCl2 concentrations in the standard internal solution were
changed to 3.7 and 2.6 mM (free [Mg2+] = 2 mM),
respectively. In some experiments, intracellular solution contained (in
mM) 110 Cs-glutamate, 7 MgCl2, 5 Mg · ATP, 0.5 CaCl2, 10 Cs-EGTA, and
30 HEPES, pH 7.2 adjusted with CsOH. The calculated free
[Ca2+] and [Mg2+] were 10 nM and 5 mM,
respectively. This solution was used to block MIC channels (18,
26, 34, 40). Whole cell ICRAC was
detected by applying a 100- or 320-ms voltage ramp from 100 to 100 mV
while the cell was held at
40 mV at a frequency of 1 or 0.2 Hz. The
currents measured when the cells were perfused by CFS were used as leak
current for subtraction to eliminate possible MIC current contamination
(34).
INAD expression and purification. Truncated inad gene produced by NcoI-PstI restriction endonuclease digestion of pCMV4/InaD was ligated into pBADmychisA (Invitrogen) to generate pBADInaDTr. An 890-bp PCR product generated from pCMV4/InaD with the primers Pr.INAD3'END (5'-TCG TCT CTA AAG CTT GGG TGC CTC-3') and Pr.INAD3 (5'-ATG GTC ATC TAT GGC AAG C-3') was digested with HindIII and ligated to PstI-HindIII-digested pBADInaDTr. This linear construct was digested with PstI and self-ligated to produce pBADInaD. Nucleotide sequences of both pBADInaD and pBADInaDTr were confirmed at the Iowa State University DNA Sequencing Facility (Ames, Iowa).
INAD expression from pBADInaD was induced in logarithmically growing Escherichia coli TOP10 cells with 0.2% L-arabinose in Luria-Bertani broth with 100 µg/ml ampicillin for 4 h at 37°C. Cells from 6 liters of induction medium were collected and resuspended in 10 ml of lysis buffer (6 M guanidine · HCl, 20 mM Na · phosphate, pH 7.4, 0.5 M NaCl, 0.1 mM PMSF, 0.1 µg/ml leupeptin, and 0.1 µg/ml Pefabloc) with gentle shaking on ice for 30 min and then disrupted by sonication. Cell debris was pelleted, and soluble proteins were renatured at 4°C by dialysis, first against dialysis buffer (1 M guanidine · HCl, 0.1 mM PMSF, 0.1 µg/ml leupeptin, and 0.1 µg/ml Pefabloc) and twice against water and protease inhibitors (0.1 mM PMSF, 0.1 µg/ml leupeptin, and 0.1 µg/ml Pefabloc). Precipitated proteins were removed by centrifugation, and the supernatant was brought to 30% saturation with ammonium sulfate at 4°C. Precipitated proteins were pelleted, and the supernatant was brought to 40% ammonium sulfate saturation at 4°C. Precipitated protein was again pelleted and then resuspended in loading buffer (20 mM Na · phosphate, pH 5.0, 0.5 M NaCl). Insoluble protein was removed by centrifugation, and the supernatant was applied to a HiTrap chelating column (Pharmacia Biotech) preequilibrated with loading buffer. The column was washed with 10 bed volumes of loading buffer, and INAD was eluted with 5 bed volumes of elution buffer (20 mM Na · phosphate, pH 4.0, 0.5 M NaCl). INAD was then dialyzed twice at 4°C against 1 liter of standard internal solutions for whole cell recordings, with precipitated proteins removed by centrifugation. Final protein concentrations were determined by Bradford assay using a BSA standard curve. The supernatant typically contained a protein concentration of 50-100 µg/ml and was used in the electrophysiological experiments without further dilution.CIF preparation. We used a previously described procedure to prepare CIF from human platelets (8).
Data analysis.
Patch-clamp data were analyzed using pCLAMP 8 (Axon, Foster City, CA).
The activation time course of CRAC channels was fitted to equations
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RESULTS |
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Whole cell ICRAC can be isolated by a leak current
subtraction method.
Several groups have recently demonstrated that omission of
Mg2+ or Mg · ATP in the whole cell
pipette can activate a cation current termed
Mg2+-nucleotide-regulated metal ion (MagNum) current
(11) or Mg2+-inhibited cation (MIC) current
(34) in both Jurkat and RBL cells that is presumably
encoded by LTRPC7/TRP-PLIK/TRPM7 gene (11, 18, 26, 34).
Even though MIC channels can be inhibited intracellularly by
Mg2+ alone with an IC50 of 0.5 mM, they still
can be sporadically activated during whole cell recordings when
intracellular free [Mg2+] is <3 mM (34).
Prakriya and Lewis (34) have suggested that pure
ICRAC can be isolated from possible
MIC-contaminated current by subtracting a leak current taken when cells
are exposed to a Ca2+-free but Mg2+-containing
solution. To validate this method, we compared the divalent and
monovalent currents recorded with two different intracellular solutions
after the aforementioned leak current subtraction was performed. As
shown in Fig. 1A, when the
pipette contained 7 mM MgCl2 and 5 mM
Mg · ATP, a typical ICRAC
carried by Ca2+ with an inwardly rectifying current-voltage
(I-V) relationship and a reversal potential >50 mV (Fig.
1B) was spontaneously activated after whole cell break-in.
The channels activated were not permeable to Mg2+ (Fig.
1A), which is a hallmark property of CRAC channels
(18, 20, 34). Switching the bath solution from the
standard external solution to DVF invoked a larger
Na+-carried current with an inwardly rectifying
I-V relationship and a reversal potential around 50 mV,
which rapidly inactivated in ~20 s to a steady state, another
hallmark of ICRAC (2, 18, 20, 34),
further suggesting that the current is solely conducted by CRAC
channels. These results thus confirmed that high levels of
Mg2+/ATP (~5 mM) in the pipette solution could completely
block spontaneous activation of MIC channels (18, 20, 34).
As shown in Fig. 1, C and D, when the free
[Mg2+] level in the pipette was buffered to 2 mM and the
aforementioned leak current subtraction method was used,
Ca2+ and Na+ currents were recorded that were
indistinguishable from those when the pipette contained 7 mM
MgCl2 and 5 mM Mg · ATP in terms of
Mg2+ impermeability, inwardly rectified I-V
relationships for both Ca2+ and Na+ currents,
reversal potentials, and inactivation of the monovalent current. These
results suggest that the current isolated was solely conducted by CRAC
channels and confirms that this leak current subtraction method is
sufficient to eliminate possible MIC current contamination
(34). We thus used this procedure of leak current subtraction in all the following experiments.
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CRAC channels are not activated by physical interaction between
IP3R and CRAC channels.
Recent results with an IP3R blocker 2-APB have been used to
argue that SOC activation is due to an IP3- and/or
depletion-mediated conformational change in the IP3R
(22). The relative unimportance of the IP3R as
an activator for CRAC channels is suggested by the observation that
ICRAC spontaneously and normally developed during whole cell dialysis even in the presence of the IP3
receptor antagonist heparin (0.5 mM) in the pipette solution (Fig.
2A; delay = 95 ± 6.1 s for heparin and 100 ± 8.4 s for
control, P > 0.1;
= 149.4 ± 20.9 s
for heparin and 149.5 ± 34.1 s for control, P > 0.25). These results are also consistent with
previous reports (1, 5). Similar results were observed
with another IP3R inhibitor, xestospongin C
(17) (20 µM in pipette solution, data not shown). Thus,
if the IP3R is involved in CRAC activation, a
conformational change due to IP3 seems not to be required.
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CRAC channels do not require the continued presence of a diffusible
factor once they are activated in whole cell configuration.
Although our previous results suggested that CRAC channels are
activated by CIF (8, 44), how CIF activates CRAC channels is unknown. If CRAC channels are activated by direct binding of CIF,
then ICRAC might be predicted to inactivate
after a period of time in whole cell recordings. This might occur
because the concentration of CIF would decrease if its rate of
synthesis fell behind its rate of removal due to degradation and/or the
exchange between the cytosol and pipette solution. In contrast to this prediction, as shown in Fig. 3, after
ICRAC was activated by dialysis of the cytosol
by pipette solution, it could be recorded more than 120 min after whole
cell break-in (n = 4), even though the channels
underwent slow inactivation process as previously reported (27,
57). As a result of diffusion (23), this period of time should have washed out a small molecule such as CIF with a
molecular weight <1,000 Dalton (38). This might suggest
that, once activated, maintaining the CRAC channels in an open state does not require the continued presence of a diffusible molecule such
as CIF under this recording condition. In other words, CRAC channels
are unlikely activated by direct binding of CIF. Our hypothesis to
explain this is that the CRAC channel might be activated by CIF through
removal of an inhibitory molecule that otherwise keeps it in a closed
state. Krause et al. (19) have recently found that
ICRAC could be activated in the absence of
global ER store depletion by low cytoplasmic [Ca2+]. One
explanation of their results is that a low cytoplasmic [Ca2+] environment promotes the dissociation of the
putative inhibitor from the CRAC channel, which then activates. In
other words, the inhibitory factor associates with the CRAC channel in
a Ca2+-dependent manner. Thus what is the putative
inhibitory factor for CRAC channels?
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INAD inhibits CRAC channels in a
Ca2+-dependent manner.
Detection of light by photoreceptors in the eye of
Drosophila requires activation of a cation channel that
includes transient receptor potential (TRP) channel subunits
(54). Mammalian cells express homologues of TRP, and
certain of these can function as SOCs (3). Indeed, there
is evidence that mammalian TRPs may be components of CRAC channels
(32, 51, 56). In Drosophila, inactivation-no
after potential D (INAD), a multivalent PDZ domain-containing protein,
functions as a scaffold protein as well as a regulator of the TRP/TRPL
channel (21, 41, 43, 48, 49, 53). In particular, it
associates with TRP/TRPL through one or two of its PDZ domains with a
peptide motif, -S/T-X-V/I, in the carboxyl (COOH) terminal cytoplasmic
domain of TRP/TRPL (25, 42), as well as the COOH terminus
itself (21). This leads to deactivation of TRP and/or TRPL
Ca2+ channel activity (21, 42). A recent study
further demonstrated that overexpression of INAD inhibits TRP channels
(10). Interestingly, we have found a number of S/T-X-V/I
motifs as well as another PDZ domain-binding motif, -x-
, where
is a hydrophobic amino acid, in the COOH-terminal domain of
TRP1-6 of the mammalian TRP family (data not shown). Indeed, TRP4
and TRP5 can bind to a PDZ-containing scaffold protein,
Na2+/H+ exchanger regulatory factor (NHERF)
(46). In addition, we also found a putative EF-hand
Ca2+-binding motif from G279-I291 in the second PDZ domain
of INAD (NH2-GVDPNGALGSVDI-COOH). Consequently, we tested
INAD as a surrogate inhibitor of ICRAC.
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DISCUSSION |
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Several groups have recently demonstrated that low levels of free [Mg2+] (<3 mM) in the pipette solution may activate MIC and ICRAC spontaneously and simultaneously (11, 18, 34) in both Jurkat and RBL cells during whole cell recordings. MIC may be responsible for the previously claimed single-channel current of CRAC channels when divalent cations are taken from both sides of the plasma membrane (4, 9, 13). Single-channel conductance of CRAC channels for Na+ in the absence of extracellular Ca2+ was estimated at 0.2 pS by noise analysis (34), which is beyond the current resolution of patch-clamp recording techniques. Although ICRAC and MIC can be simultaneously and spontaneously activated during whole cell recordings when intracellular free [Mg2+] is low, there are still ways to separate ICRAC and MIC by using the different properties of these currents. In this study we isolated ICRAC from possible MIC-contaminated current by subtracting the leak current recorded while cells were exposed to Ca2+-free but Mg2+-containing solutions after ICRAC was fully activated, as suggested previously by Prakriya and Lewis (34) on the basis that MIC channels are equally permeable to Ca2+ and Mg2+ whereas CRAC channels are only permeable to Ca2+. The success of this method is manifested by the fact that the isolated currents were indistinguishable from currents recorded when MIC was presumably completely blocked by high concentrations of Mg/ATP, in terms of current size, inwardly rectifying I-V relationship, and inactivation of monovalent cation currents (Fig. 1).
It has recently been suggested that the IP3R is involved in the activation of some SOCs (15, 17, 35). However, this appears not to be the case for CRAC channels on the following basis. First, inclusion of the IP3R inhibitor heparin in the whole cell pipette failed to affect the spontaneous activation of ICRAC (Fig. 2A), which is consistent with previous reports (1, 5). Another IP3R inhibitor, xestospongin C, also could not inhibit ICRAC during whole cell recordings when applied from either the intracellular or extracellular side of the plasma membrane (unpublished observation). Second, knockout of all isoforms of IP3R in DT40 cells fails to affect ICRAC activation in these cells (33, 45) (but see Ref. 16).
Although 2-APB can efficiently inhibit CRAC channels, it apparently exerts the effect by directly blocking the CRAC channel extracellularly, instead of disrupting the physical interaction between CRAC channels and IP3R. Some of the previous evidence for SOC/IP3R coupling (22) can now be explained by the finding that 2-APB is a potent and direct CRAC channel blocker. Thus caution needs to be taken when interpreting data with 2-APB. This, of course, does not negate the possibility that the IP3R directly couples to and regulates certain SOCs or mammalian TRP channels such as TRP3 that do not show the precise features of ICRAC (17, 37, 50).
On the basis of the present results with INAD, it is tempting to
speculate that mammalian homologues of this protein are key elements in
CRAC channel regulation. These data lead to a model of the signaling
mechanism that couples ER Ca2+ store depletion in mammalian
cells with plasma membrane CRAC channels (Fig.
6). Specifically, there is
Ca2+-dependent conformational coupling between a putative
INAD homologue (which we termed MINAD, for mammalian INAD) and one or
more mammalian TRP subunits comprising the CRAC channel. This occurs
through interactions between the TRP and certain PDZ domains on MINAD, which also may serve to anchor the complex to the cytoskeleton (52). In the intact cell, Ca2+ and MINAD
function to maintain CRAC channels in the closed state until a
diffusible store-depletion signal, CIF, causes the complex to
dissociate and CRAC channels to open. After refilling of the stores and
the decay of CIF, the complex is reestablished and CRAC channels close.
In the absence of CIF, low local [Ca2+] either
physiologically or experimentally due to passive dialysis may also
result in disassociation of MINAD from the CRAC channel and, thus,
ICRAC activation. In this light, it is
interesting to note the putative EF-hand Ca2+-binding motif
(G279-I291) in the second PDZ domain of INAD. We hypothesize that
dissociation of Ca2+ from this site due to low local
Ca2+ levels induces a conformational change in MINAD and,
thus, dissociation of MINAD from the CRAC channels. This may well
explain the finding by Krause et. al (19) that
ICRAC can be activated by low levels of
cytoplasmic Ca2+ independently of store depletion.
Therefore, CIF might serve as a coarse regulator of CRAC channels while
the local cytoplasmic Ca2+ serves as a fine tuner.
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This model has some very attractive features that add to its credibility. First, TRP mammalian homologues have PDZ domain-binding motifs, as mentioned before. Second, INAD homologues exist in mammalian cells (31). Most interestingly, a PDZ domain-containing mammalian protein, NHERF, which interacts with the cytoskeleton, was recently found to bind to the TRP4 and TRP5 proteins (46). Third, the association/dissociation of CRAC channels and INAD occurs at physiologically relevant [Ca2+] (~100 nM). Fourth, overexpression of INAD inhibits the activation of TRP channels by store depletion (10).
These results also provide further strong support for the existence of CIF. The interaction with INAD may well provide a means to purify and identify this elusive substance. In addition, the "secretory vesicle/kiss and run" model might now be explained by the necessity of delivering vesicles producing CIF to the vicinity of the CRAC channel/INAD-like complex. Finally, results on some SOC with agents that affect the cytoskeleton (30, 55) may well be due to alterations in PDZ domain interactions with cytoskeletal elements, which are known to occur with INAD and other PDZ domain-containing proteins (52).
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ACKNOWLEDGEMENTS |
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We thank Dr. B. Shieh (Vanderbilt University) for providing the pCmv4/INAD clone and Dr. K. Mikoshiba (Tokyo University) for the generous gift of 2-APB.
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FOOTNOTES |
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This work was supported in part by National Institutes of Health Grants AI-37670 and HL-68806 (to J. E. Blalock) as well as DK-55647 and HL-68806 (to J. E. Blalock and R. B. Marchase), Juvenile Diabetes Foundation Grant 2000-137 (to R. B. Marchase and J. E. Blalock), and a grant from the C. C. Wu Foundation in Hong Kong (Z. Su).
Address for reprint requests and other correspondence: J. E. Blalock, Dept. of Physiology and Biophysics, Univ. of Alabama at Birmingham, MCLM 898, 1918 Univ. Blvd., Birmingham, AL 35294-0005 (E-mail: Blalock{at}uab.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 16, 2002;10.1152/ajpcell.00183.2002
Received 22 April 2002; accepted in final form 8 October 2002.
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