Store-Operated Calcium Channels (Current Topics in Membranes)
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However, this whole oocyte current had a very different current-voltage relationship from the patch current reported earlier , suggesting that the patch current was not a purely store-operated one. Yao et al. Excision of the patch current did not result in loss of activity, leading these authors to conclude that a diffusible messenger was not central to the gating of the channels As in the earlier study by Parekh et al.
Hence, it is not clear whether a diffusible messenger is involved in store-operated entry in oocytes. In RBL cells, Fasolato et al. If stores were depleted shortly after the onset of whole cell recording, large I CRAC could be generated. But if stores were dialyzed for a few tens of seconds before store depletion, the size of I CRAC was significantly reduced.
Correcting for cell size and series resistance indication of size of connection between the patch pipette and the cytosol , Fasolato et al. The ability of store depletion to activate the current was not detectably impaired even if stores were depleted 10—15 min after the onset of whole cell recording 87 , Hence, the activation mechanism of I CRAC does not seem to require a small, freely mobile molecule that preexists in the cytosol.
One should note, though, that such direct physical coupling does not occur in either cardiac or smooth muscle cells. It would be important to see whether rapid increases in InsP 3 can activate a proportion of the CRAC channels within a fraction of a second in other systems. The slow activation of I CRAC in spite of rapid store depletion led Gill and colleagues to propose the secretion-like coupling model.
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Instead, upon store depletion, trafficking of peripheral ER to the plasma membrane occurs, and when the two membrane systems are optimally juxtaposed, the coupling reaction takes place. The secretion-like coupling model predicts that first, store-operated channels should be activated directly by InsP 3 receptors and that functional InsP 3 receptors are required for the maintenance of store-operated entry, and second, maneuvers that interfere with trafficking of the ER to the plasma membrane should impair store-operated influx.
There is evidence to support each of these predictions, but there is also evidence that cannot be easily reconciled with the model. We shall discuss each prediction in turn. Three lines of evidence have led to the suggestion that store-operated channels can be activated by InsP 3 receptors. Second, InsP 3 receptors seem to activate certain endogenous store-operated channels in excised patches , In the platelet study, coimmunoprecipitation only occurred after store depletion, and no binding of TRPC1 channels with InsP 3 receptors was evident after stores had been allowed to refill One note of caution is that the specificity of the antibodies has not been extensively characterized and is in fact the matter of some debate see discussion in sect.
Kiselyov et al. This coupling was mediated by the cytoplasmic NH 2 -terminal domain of type I InsP 3 receptor ; see sect. Surprisingly, the coupling was somewhat promiscuous because ryanodine receptors could also activate the channels Whether TRPC3 channel activity requires InsP 3 and, more fundamentally perhaps, if the channels are indeed store-operated are controversial issues.
Although it seems that TRPC3 channels can be store-operated when expressed at low levels, most studies do not support a requirement for InsP 3 in channel gating. However, subsequent stimulation of muscarinic receptors opened the TRPC3 channels and in a manner that was not prevented by inhibiting InsP 3 receptors with heparin In both cell types, TRPC3 could be activated not by store depletion but by diacylglycerol analogs instead.
Store-Operated Calcium Channels
Store-operated single-channel events have been observed in cultured bovine aortic endothelial cells Channel activity in inside-out patches could be sustained for a couple of minutes by adding InsP 3 to the cytoplasmic side of the patch, and this was prevented by heparin. Another store-operated current thought to be gated by InsP 3 receptors is the I min of A epidermal cells , Single-channel activity is lost upon patch excision but can be rescued by application of InsP 3. In inside-out patches, channel activity is potentiated by addition of microsomes enriched in InsP 3 receptors.
Moreover, I min channel activity is potently blocked by the InsP 3 receptor antagonist heparin First, Sugawara et al. Recent patch-clamp experiments have demonstrated that the mutant cells express I CRAC at normal levels Furthemore, several studies have found that dialysis with heparin, a competitive antagonist of InsP 3 receptors, fails to affect the ability of I CRAC to activate 13 , 89 , Because of its much larger size, heparin entered the cells more slowly, but as it accumulated in the cytoplasm, it displaced bound InsP 3 from InsP 3 receptors.
I CRAC could be activated once more. Under these conditions, heparin would presumably still be occupying the InsP 3 receptors, yet the current could be evoked again. However, dialysis of RBl-1 cells with ruthenium red, an inhibitor of ryanodine-sensitive channels, together with heparin failed to affect the rate or extent of activation of I CRAC A crucial observation that is often regarded as solid evidence for the secretion-like coupling model is that stabilization of the cytoskeleton, specifically the cortical actin network just below the plasma membrane, inhibits the activation of store-operated entry , It has been suggested that the cortical actin barrier prevents ER from making contact with the plasma membrane, and hence, InsP 3 receptors on the stores are unable to activate the store-operated channels.
In RBL-1 cells for example, altering the cytoskeleton induced marked changes in cell morphology and distribution of actin, but neither the rate of development nor extent of I CRAC was affected It is well established that the morphology of the ER is maintained through a tight interaction with microtubules Disruption of the microtubular network causes retraction of the peripheral ER that lies close to the plasma membrane towards the cell center. However, prolonged exposure to nocodazole, which disrupts microtubules, failed to affect the development of I CRAC An important prediction of the secretion-like coupling model is that it requires intimate association between the ER and plasma membrane.
With the use of the method of whole cell ballooning 13 , which is thought to separate the plasma membrane from underlying structures through the application of strong positive pressure through the patch pipette, the ability of I CRAC to activate was unaffected if stores were emptied after cell inflation had occurred. One might have expected cell ballooning to interfere with activation of I CRAC if a trafficking model were to be operating.
Collectively, the idea that CRAC channels are activated by conformational coupling to InsP 3 receptors in the ER membrane seems unlikely at least in the majority of instances.
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The vesicular fusion hypothesis suggests that store-operated channels are not in the plasma membrane at rest but are inserted into the membrane upon store depletion via an exocytotic mechanism. There is good evidence for regulated fusion of TRPC channels 29 , although as discussed below, their role in store-operated entry is not well established.
Strictly speaking, the fusion model should not be considered an activation mechanism in its own right because it does not address the key question of the activation signal. But a consequence of this is insertion of channels into the plasma membrane. However, neither of these tools is specific for targeting secretory mechanisms, and different conclusions have been reached by others. Effects of cytochalasin D seem cell-type specific in that it fails to affect store-operated entry in several systems 13 , , However, botulinum neurotoxins B and E and tetanus toxin were all without effect The effects of the neurotoxins were not mimicked by brefeldin A, indicating that an action on constitutive exocytosis was not involved.
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On the other hand, the current was seen if seals were formed after stores had been depleted. Excision of the patch resulted in a slight increase in current, arguing against a central role for a small diffusible messenger in maintaining channel activity. However, there are some puzzling features about the currents measured. The current recorded in cell-attached patches appeared curvilinear with a decreasing conductance as membrane potential hyperpolarized Although a characterization of the patch current was not presented, it would seem that the current measured in the whole oocyte compared with that seen in patches may not represent the same population of channels.
In fura 2-loaded HEK cells, it was also concluded that activation of store-operated entry involved vesicular fusion 3. In contrast to the oocyte study , tetanus toxin also reduced calcium entry in HEK cells 3.
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Such long exposure times would not distinguish between a role for vesicular fusion in the direct activation of store-operated influx as opposed to maintaining quiescent channels or other signaling proteins in the plasma membrane via constitutive exocytosis. First, it is often difficult to distinguish between constitutive and regulated exocytosis, especially when cells have been exposed to clostridial neurotoxins for a few hours.
In HEK cells, brefeldin A impaired store-operated entry with a similar time course and to a similar extent to that seen in the presence of tetanus toxin 3. In oocytes however, store-operated entry was unaffected by 20 h of treatment with brefeldin A Hence, in some nonexcitable cells, vesicle trafficking can be relatively fast. In these cases, it is therefore difficult to dissect out a regulated exocytotic event from a constitutive process.
Second, inhibition of exocytosis will normally permit endocytosis to continue, at least to some extent. Hence, the cell surface area will fall, and this must be monitored by taking into account the total plasma membrane surface area. Unless electrophysiological measurements are made to measure membrane capacitance , it is difficult to correct for this. There is also experimental evidence that does not fit with vesicular fusion as the ubiquitous mechanism for activation of store-operated influx. SNAP, the target of botulinum toxin, is not expressed in nonexcitable cells, essentially being restricted to neurons and neuroendocrine cells.
Hence, the inhibitory effect of botulinum toxin on store-operated entry described in Reference is unexpected as its substrate apparently should not be present. Indeed, Scott et al. Expression of a truncated form of SNAP failed to affect store-operated entry, whereas it impaired cycling of transferrin receptors. More dramatically, expression of a mutant NEM-sensitive factor NSF construct inhibited membrane trafficking events in general including recycling of transferrin receptors to the plasma membrane, retrograde traffic to the Golgi complex, and intracellular events including fusion of endosomes to lysosomes.
In spite of these changes, store-operated influx was unaffected. The authors concluded that the vesicular fusion model was not viable, at least in their systems A key prediction of the fusion model is that any maneuver that impairs exocytosis should interfere with the ability of I CRAC to activate.
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However, the activation of I CRAC following exposure to thapsigargin was unaffected by a similar exposure to the protein. Furthermore, a variety of toxins tetanus, botulinum neurotoxins and pharmacological agents that impair secretory events were all without effect on I CRAC. In this interesting, albeit somewhat speculative, scenario, store-operated channels open, not via an activation signal, but rather by removal of inactivation.
However, just how store refilling switches off the store-operated channels is unclear. The simplest possibility is that it reflects simple reversal of the activation mechanism. As the stores refill, the activation signal decays. Alternatively, refilling stores may send an inhibitory signal that overcomes activation. However, in light of the fact that there are so many such examples, it is worth exploring the concept that the signaling mechanism is complex and that store depletion and refilling might not control store-operated entry via the same pathway.
With this protocol, I CRAC initially increases due to the increased electrical driving force but then declines as rapid inactivation takes effect.
Recovery from inactivation is a biexponential process with time constants in the range of 10— ms. Neither the rate nor extent of fast inactivation is affected by receptor stimulation in RBL-1 cells, suggesting that the process might not be under receptor control other than through changes in the membrane potential The decline of I CRAC could be partially reversed by exposing the cells to thapsigargin, indicating that store refilling contributed to the decay.
Although thapsigargin reduces the decay of I CRAC under conditions where stores can refill, it does not fully suppress it. I CRAC still decays, albeit partially, in the presence of thapsigargin, and this occurs over a timeframe of tens of seconds 13 , , The mechanism underlying this slow inactivation is not clear. In T cells, recovery from slow inactivation is prevented by protein kinase blockers, suggesting an ATP-dependent phosphorylation might be involved in the recovery process In RBl-1 cells on the other hand, kinase and phosphatase blockers did not affect the development of slow inactivation In both RBl-1 cells and T lymphocytes, slow inactivation was much less pronounced if mitochondria were maintained in an energized state during whole cell recording , Calmodulin is a very important modulator of voltage-operated L-type calcium channels.
As with their voltage-operated counterparts, calmodulin regulation of store-operated entry has been reported. In bovine aortic endothelial cells, dialysis with calmodulin impaired, in a concentration-dependent manner, the ability of thapsigargin to activate a store-operated current The rate of development of the current was slowed almost twofold, its peak amplitude was significantly reduced, and slow inactivation was enhanced by calmodulin. A similar trend was seen in CHO cells But in some other cell types, calmodulin has been found to inactivate store-operated entry, rather than enhance it , This effect was not mimicked by overexpressing wild-type calmodulin.
The simple approach of applying inhibitors like calmidazolium is problematic if calmodulin is not free but attached to the channels, where it is much less sensitive to inhibition.