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J Physiol (2003), 553.2, pp. 387-393
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2003.055335

Activation of the store-operated calcium current I_CRAC can be dissociated from regulated exocytosis in rat basophilic leukaemia (RBL-1) cells

Daniel Bakowski, Robert D. Burgoyne* and Anant B. Parekh

	ABSTRACT

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In many cell types, the emptying of intracellular Ca²⁺ stores results in the opening of store-operated Ca²⁺ channels in the plasma membrane. However, the nature of the signal that couples store content to the opening of these Ca²⁺ channels is unclear. One model proposes that the Ca²⁺ channels are initially stored in cytoplasmic vesicles but inserted into the plasma membrane upon store depletion via a regulated exocytoytic mechanism (vesicular fusion model). Using the whole-cell patch-clamp technique to measure the store-operated Ca²⁺ current I_CRAC and the capacitance method to monitor vesicular fusion, an indicator of exocytosis, we have investigated the effects of interfering with regulated exocytosis on the ability of I_CRAC to activate. We find that the recombinant protein -SNAP^1-285, an inhibitor of exocytosis in many systems, suppresses such fusion but has no impact on the activation of I_CRAC. A variety of other manoeuvres that interfere with vesicle trafficking and exocytosis were also without effect on I_CRAC. Impairing constitutive exocytosis with brefeldin A reduced the extent of I_CRAC, but this effect was less pronounced when current density was considered instead. Activation of I_CRAC can therefore be clearly dissociated from an exocytotic mechanism, a finding that is not easily reconcilable with the vesicular fusion model.

(Received 17 September 2003; accepted after revision 27 October 2003; first published online 31 October 2003)
Corresponding author A. Parekh: Laboratory of Molecular and Cellular Signalling, Department of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Email: anant.parekh{at}physiol.ox.ac.uk

	INTRODUCTION

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In non-excitable cells, one major source for Ca²⁺ influx is through the store-operated pathway (formerly called capacitative Ca²⁺ entry) where the process of emptying intracellular InsP₃-sensitive calcium stores opens Ca²⁺ channels in the plasma membrane (Parekh & Penner, 1997; Putney & McKay, 1999). The mechanism that links store depletion to activation of the Ca²⁺ channels is unknown. To date, three models have been put forward to explain this process (reviewed in Parekh & Penner, 1997; Venkatachalam et al. 2002): (i) conformational coupling and the related secretion-like coupling which involve an interaction between InsP₃ receptors on the intracellular stores and the Ca²⁺ channels in the plasma membrane, (ii) generation of a diffusible messenger as a consequence of store depletion, and (iii) insertion of vesicles containing the Ca²⁺ channels into the plasma membrane upon store depletion. We have previously reported that the secretion-like coupling model is unlikely to account for the activation of store-operated Ca²⁺ influx in rat basophilic leukaemia (RBL) cells (Bakowski et al. 2001). Here, we have examined the vesicular fusion model. Two types of exocytosis are known: regulated and constitutive. In regulated exocytosis, vesicles accumulate intracellularly and only fuse with the plasma membrane in response to a regulatory signal. In constitutive exocytosis, the vesicles constantly fuse and this is not under tight control. Despite these differences, the final molecular mechanisms underlying fusion are highly conserved between the two processes.

It has been recently been reported that expression of botulinum toxin A or overexpression of a dominant-negative SNAP-25 mutant reduced store-operated Ca²⁺ influx in Xenopus oocytes (Yao et al. 1999). Because interfering with constitutive exocytosis did not mimic the effects of the neurotoxin or the SNAP-25 mutant, at least over several hours, it was concluded that activation of store-operated entry occurred through insertion of calcium channels (or a key regulator) into the plasma membrane via a regulated exocytotic mechanism very similar to that seen in neurons. A similar conclusion was reached from studies in HEK 293 cells where botulinum toxin A and tetanus toxin could both suppress store-operated Ca²⁺ entry in fura 2-loaded cells (Alderton et al. 2000).

Using the capacitance technique to track regulated exocytosis in single RBL cells (Artalejo et al. 1998), we have examined whether tools which inhibit such fusion events also suppress activation of I_CRAC, as would be predicted by the vesicular fusion model for CRAC channel activation. We find that I_CRAC can be activated normally despite suppression of exocytosis. A simple vesicular fusion model for CRAC channel activation, involving known components of the exocytotic apparatus, is unlikely to account for store-operated Ca²⁺ entry, at least in RBL-1 cells.

	METHODS

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RBL-1 cells, which were bought from American Tissue and Cell Culture, were cultured as previously described (Fierro & Parekh, 1999; Bakowski et al. 2001).

Patch-clamp experiments were conducted in the tight-seal whole-cell configuration at room temperature (20-25 °C) as previously described (Fierro & Parekh, 1999). Sylgard-coated, fire-polished pipettes had DC resistances of 3.5-5 M when filled with standard internal solution containing (mM): caesium glutamate 145, NaCl 8, MgCl₂ 1, EGTA 10, Hepes 10, Mg-ATP 2, pH adjusted to 7.2 with CsOH. A correction of +10 mV was applied for the liquid junction potential that arose from this glutamate-based internal solution. In some experiments (Fig. 1), cells were dialysed with a pipette solution in which Ca²⁺ was strongly buffered at ~120 nM (10 mM EGTA, 4.6 mM CaCl₂). Extracellular solution contained (mM): NaCl 145, KCl 2.8, CaCl₂ 10, MgCl₂ 2, CsCl 10, glucose 10, Hepes 10, pH adjusted to 7.4 with NaOH. I_CRAC was measured by applying voltage ramps (-100 to +100 mV in 50 ms) at 0.5 Hz from a holding potential of 0 mV (Fierro & Parekh, 1999). Currents were filtered using an 8-pole Bessel filter at 2.9 kHz and digitised at 100 µs, and normalised by dividing the amplitudes (measured from the voltage ramps at -80 mV) by the cell capacitance. Capacitative currents were compensated before each ramp using the automatic compensation of the EPC 9-2 amplifier. All leak currents were subtracted by averaging the first few ramp currents (usually two), and then subtracting this from all subsequent currents.

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Figure 1. -SNAP1-285 impairs Ca2+ -dependent exocytosis A, whereas a robust capacitance increase can been seen following dialysis with 10 µM Ca2+, the response is substantially reduced by including 42 µg ml-1 -SNAP1-285 in the pipette solution. B, aggregate data comparing secretory responses between control cells, those exposed to -SNAP1-285 and those in which -SNAP1-285 had first been boiled in order to denature the protein.

Capacitance recordings, using the EPC 9-2 amplifier together with PULSE software (HEKA, Lambrecht, Germany) were carried out using the whole-cell patch-clamp technique at room temperature as previously described (Artalejo et al. 1998). Membrane capacitance was measured with the software lock-in extension of the Pulse software, using the Since + DC technique with a 50 mV peak-to-peak sinusoid stimulus from a DC holding potential of -60 mV, applied at 1 kHz. Cells were dialysed with an internal solution containing (mM): caesium glutamate 145, NaCl 8, MgCl₂ 1, Mg-ATP 2, GTPS 0.3, Hepes 10, HEDTA 1.5 mM, Ca-HEDTA 3 mM, pH adjusted to 7.2 with CsOH. Ca²⁺ was buffered at 10 µM. Cells were clamped at -60 mV to suppress activation of the GTPS-activated Na⁺ conductance (Artalejo et al. 1998).

The C-terminal mutant -SNAP^1-285 was prepared in E. coli as a his-tagged protein and purified as described previously (Barnard et al. 1997).

Drugs were applied locally by means of positive pressure applied to an application pipette placed within 20 µm of the cell. Thapsigargin was purchased from Alomone Laboratories. All other chemicals were purchased from Sigma. Data are presented as mean ± S.E.M., and statistical evaluation was carried out using Student's unpaired t test. * denotes P < 0.01.

	RESULTS

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-SNAP mutant inhibits regulated exocytosis in RBL-1 cells

The peripheral membrane protein -SNAP plays a key role in regulated secretion (Burgoyne & Morgan, 2003). -SNAP and the ATPase NSF (NEM-sensitive factor) bind to a 7S complex composed of the three proteins syntaxin, SNAP-25 and VAMP. This 7S complex is thought to be important for docking vesicles to the plasma membrane. Binding of both SNAP and NSF to the 7S complex transiently form a 20S complex which then disassociates due to stimulation of the ATPase activity by SNAP. This disassociation is considered to underlie vesicle priming and is essential to maintain an active pool of free SNARE proteins.

In all systems so far studied, altering the levels of -SNAP has quite dramatic effects on exocytosis (DeBello et al. 1995; Morgan & Burgoyne, 1995; Burgoyne & Morgan, 1998; Xu et al. 1999). In addition, exocytosis and various other SNARE-mediated vesicle fusion events are strongly inhibited by C-terminal -SNAP mutant proteins like -SNAP^1-285, which cannot activate the ATPase of NSF and bind irreversibly to the SNARE complex (Barnard et al. 1997; Christoforidis et al. 1999; He et al. 1999).

We used capacitance recordings, a direct measure of vesicular fusion (Neher & Marty, 1982), to examine the effects of recombinant -SNAP^1-285 on regulated exocytosis from single RBL-1 cells. Figure 1A shows a typical control recording () in which a cell was dialysed with a pipette solution containing 10 µM Ca²⁺ and GTPS (Artalejo et al. 1998). Following break-in, the membrane capacitance increased gradually but continuously over several tens of seconds. The mean capacitance increase, averaged from seven cells, is shown in Fig. 1B. Six of the seven control cells responded by generating a response > 0.3 pF (2-5 % resting capacitance), and only one failed to exhibit clear vesicular fusion. Inclusion of -SNAP^1-285 in the recording pipette suppressed exocytosis (Fig. 1A, ; pooled data in Fig.1B; P < 0.01). Six out of seven cells now failed to generate a detectable response, whereas the responder was similar to the controls. The inhibitory effect of -SNAP^1-285 was largely prevented by boiling it at ~100 °C for a few minutes (Fig. 1B, n = 6).

- SNAP^1-285 does not affect the extent of activation of I_CRAC

Since -SNAP^1-285 substantially inhibited regulated exocytosis, we next investigated whether I_CRAC was also suppressed by this inhibitory protein in the same cell type. Cells were dialysed with a pipette solution in which Ca²⁺ was strongly buffered at 120 nM to prevent spontaneous depletion of stores, and 2 µM thapsigargin was applied after 120 s of whole cell dialysis (series resistance was between 5 and 8 M). After a delay of almost 50 s, I_CRAC developed to reach a maximal amplitude within a further 300 s (Fig. 2A, ). The I-V relationship, taken at 410 s, is given in Fig. 2B. Pooled data showing the amplitude and the rate of development of the current are summarised in Fig. 2C and D, respectively. In the presence of -SNAP^1-285, I_CRAC could still activate (Fig. 2A, ) and the I-V relationship was indistinguishable from controls (Fig. 2B). The mean amplitude of I_CRAC in the presence of -SNAP^1-285 was not significantly reduced compared with controls (Fig. 2C), nor was the rate of development of the current (Fig. 2D).

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Figure 2. -SNAP1-285 does not affect the rate or extent of activation of ICRAC A depicts the time course of activation of ICRAC in a control cell () and in one which had been dialysed with 42 µg ml-1 -SNAP1-285, a concentration that inhibited exocytosis (Fig. 1). B depicts the current-voltage relationships for the two cells shown in A taken at steady state. C and D show aggregate data comparing the size of ICRAC between control cells and those exposed to -SNAP1-285 (C) and the half-time of development of the current for the two conditions (D).

Effects of agents that interfere with secretion on the activation of I_CRAC

The results with -SNAP^1-285 demonstrate that I_CRAC can activate under conditions where regulated exocytosis has been compromised. To probe this further, we examined the effects of a variety of tools that interfere with vesicular transport/fusion on the activation of I_CRAC. The results are summarised in Table 1.

Pre-treatment with B-581 (50 µM, 1 h), an agent that interferes with isoprenylation of small GTP-binding proteins and reduces thapsigargin-evoked Ca²⁺ entry in platelets (Rosado & Sage, 2000), was without effect on I_CRAC. In hippocampal neurones (Maletic-Savatic et al. 1998) and squid giant synapse (Llinas et al. 1991), Ca²⁺-calmodulin-dependent kinase II (CaM kinase II) enhances exocytotic events. In RBL-1 cells, however, KN-62 and cyclosporin A (which block CaM kinase II and the Ca²⁺-dependent phosphatase calcineurin, respectively) both failed to interfere with activation of I_CRAC. N-Ethylmaleimide (5 mM), which inhibits NSF and hence vesicular priming (but most likely other processes due to its lack of specificity), also did not alter the rate or extent of activation of I_CRAC. Tetanus toxin (10 nM, > 24 h), which cleaves synaptobrevin, was also without effect on development of I_CRAC, although we do not have a positive control showing that the toxin was effective in RBL-1 cells. Also included in Table 1 are previous results indicating that both GTPS and a host of small GTP-binding proteins fail to interfere with I_CRAC activation in RBL-1 cells.

Brefeldin A interferes with activation of I_CRAC

Brefeldin A inhibits constitutive exocytosis through its actions on the ADP ribosylation factor (ARF) family of small GTP-binding proteins. By inhibiting GDP-GTP exchange on ARF, brefeldin A suppresses vesicular transport from the transitional endoplasmic reticulum (ER) to the cis-Golgi cisternae. Retrograde movement from Golgi to the endoplasmic reticulum is unaffected, and so components of the Golgi apparatus are inserted into the ER. Disaggregation of the Golgi network results in the loss of both constitutive exocytosis and Golgi-derived vesicles involved in regulated exocytosis. Figure 3A compares the time course of development of I_CRAC from a control cell and from two cells pre-exposed to brefeldin A for 12 h. I_CRAC was evoked by dialysing the cells with a pipette solution containing 30 µM InsP₃ and 10 mM EGTA. In the control cell, the current was evoked without a discernible delay (< 2 s) and developed mono-exponentially to reach an amplitude of -42 pA at -80 mV. After brefeldin A treatment, one cell () failed to respond at all; the other cell did respond (), but only after a substantial delay (30 s) and the current reached a smaller steady-state amplitude. Pooled data is summarised in Fig. 3B. I_CRAC was significantly smaller in brefeldin A-treated cells (P < 0.001). That brefeldin A was indeed interfering with constitutive exocytosis was seen by the fact that the membrane input capacitance was significantly smaller in brefeldin A-treated cells compared with controls (Fig. 3C, P < 0.01). A smaller cell would presumably contain less functional CRAC channels, and this could explain the smaller macroscopic current in the presence of brefeldin A. However, after normalising the size of the current to membrane capacitance (i.e. current density, pA pF^-1), brefeldin A-treated cells still gave a smaller value (Fig. 3D, P < 0.01)). Brefeldin A-exposed cells generated I_CRAC after a longer delay (P < 0.05) and the current tended to develop more slowly (Fig. 3E), although this was not significant (P < 0.1). The inhibitory effects of brefeldin A were time dependent in that pre-incubation with the drug for 2 h failed to alter the rate or extent of I_CRAC (data not shown; see also McCloskey & Zhang, 2000). We also activated I_CRAC in control cells and then applied brefeldin A once the current had reached a steady state level. I_CRAC was unaffected by the drug for up to 300 s (3/3 cells, data not shown).

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Figure 3.Brefeldin A reduces ICRAC A shows the time course of development of ICRAC in a control cell () and in two cells pre-exposed to brefeldin A for 12 h (, ). In B, the mean whole cell current is shown for control cells and for those exposed to brefeldin and the corresponding capacitance measurements, an indication of cell size, are summarised in C. In D, the size of ICRAC has been normalised to cell size by dividing the current (B) by the capacitance (C). E compares the kinetics of activation of ICRAC for the two conditions. Panels F-J are identical to A-E but summarise data from preparations of RBL-1 cells in which current density was not significantly reduced by brefeldin A.

In some other cell preparations (Fig. 3F-J), the absolute size of I_CRAC was smaller in brefeldin A-treated cells compared with controls (Fig. 3F and G, P < 0.01 for brefeldin A-treated versus control), as was input capacitance (Fig. 3H, P < 0.05). However, the current density was not significantly different between control cells and those exposed to brefeldin A (P < 0.2, Fig. 3I). Nevertheless, both the delay before I_CRAC activated as well as the time to peak were significantly slower in brefeldin A-treated cells (Fig. 3J). The reason for this slower development of I_CRAC is unclear but might indicate a requirement for intact endoplasmic reticulum/Golgi apparatus in the kinetics of activation.

	DISCUSSION

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Our findings reveal that I_CRAC can be activated normally under conditions where regulated exocytosis is suppressed. The recombinant -SNAP^1-285 C-terminal mutant used here has been found to inhibit vesicular fusion events at the plasma membrane in many systems (e.g. Barnard et al. 1997; He et al. 1999) and we now show that this is also the case for RBL-1 cells. This mutant protein and biochemically related C-terminal -SNAP mutants inhibit all SNARE-mediated intracellular fusion events that have been tested to date including not only exocytosis but also homotypic endosome fusion (Christoforidis et al. 1999) and transport from endoplasmic reticulum to Golgi and within the Golgi complex (Lanoix et al. 1999; Band et al. 2001). Because -SNAP^1-285 did not interfere with activation of I_CRAC, this would indicate that the activation mechanism does not depend on a regulated exocytotic pathway or indeed any kind of SNARE-dependent pathway. Although we cannot discard the possibility that vesicles containing CRAC channels might be inserted through an entirely novel mechanism, it appears that all intracellular fusion events that have been characterised so far involve a SNARE-based machinery (McNew et al. 2000). One caveat that should be noted is that we cannot rule out formally that CRAC channel-containing vesicles are already docked and are beyond a SNARE-requiring step. It would be surprising, however, for a portion of the vesicles not to be in an inhibitable state as is the case for other vesicle fusion events. In addition, the original evidence suggesting a vesicle fusion model for CRAC activation was based on the use of reagents that would inhibit SNARE function prior to vesicle docking (Yao et al. 1999). Consistent with our -SNAP^1-285 findings, a variety of tools which interfere with different components of the secretory pathway all failed to affect I_CRAC (Table 1). Admittedly, not all these agents are specific in their action but, nevertheless, none of them provide support for a vesicular fusion model in RBL cells. In HEK 293 cells, intracellular injection of either botulinum toxin/A1c or tetanus toxin inhibited Ca²⁺ entry following store depletion with cyclopiazonic acid in fura 2-loaded cells (Alderton et al. 2000). However, in these experiments Ca²⁺ influx was not measured directly and effects both on the membrane potential and Ca²⁺ clearance mechanisms could also have influenced the size of the Ca²⁺ signal. Moreover, Ca²⁺ influx was measured 2 to 3 h after toxin injection, which would not permit clean dissection between a channel insertion mechanism for activation of store-operated channels and constitutive exocytosis. Indeed, disruption of constitutive exocytosis by exposure to brefeldin A for 4 h inhibited store-operated entry to a level indistinguishable from that seen in the presence of tetanus toxin (Alderton et al. 2000).

It is possible that different cell types use different mechanisms to activate store-operated Ca²⁺ entry and a vesicular fusion mechanism could be employed in some preparations (e.g. Xenopus oocytes, Yao et al. 1999; Alderton et al. 2000) but not in RBL cells. However, the fusion model for oocytes is itself controversial. Others have concluded that such a model did not account for store-operated Ca²⁺ influx in Xenopus oocytes (Gregory & Barritt, 1996). Alternatively, because different store-operated Ca²⁺ entry pathways have been described, it is possible that these different influx pathways are activated via distinct mechanisms. I_CRAC is the most widespread and best characterised of store-operated Ca²⁺ currents, but it is not the only one. Interestingly, the calcium current reported in the oocyte (Yao et al. 1999) was very different from both I_CRAC and other store-operated currents that have been described. The current-voltage relationship was linear in the whole oocyte, but outwardly rectifying in giant macropatches from the same cell (Yao et al. 1999). Moreover, the oocyte patch current was very unstable at moderately negative voltages (-60 mV), potentials where most of the calcium influx in an oocyte occurs. Finally, our results with brefeldin A demonstrate that care is needed in interpreting results in which vesicular trafficking has been compromised. Had we measured only whole-cell currents, then we would have found rather dramatic effects of brefeldin A on the extent of I_CRAC activation. However, brefeldin A also reduced cell size and the effects on I_CRAC were less dramatic when we corrected for this by considering current density instead. Interestingly, certain treatments reduced both Ca²⁺ entry and membrane capacitance in the oocyte study by Yao et al. (1999), but Ca²⁺ influx was not corrected for any change in capacitance. For these treatments at least, the effects of interfering with exocytosis on store-operated entry may have been significantly overestimated.

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Acknowledgements

This work was supported by an MRC programme grant to A.B.P. A.B.P.is a Lister Institute Senior Research Fellow and holds the Monsanto Senior Research Fellowship at Exeter College, Oxford.

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