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Capacitative Calcium Entry

Jaclyn R. Holda, Andrey Klishin, Marina Sedova, Jörg Hüser and Lothar A. Blatter

J. R. Holda, A. Klishin, M. Sedova, J. Hüser, and L. A. Blatter are in the Dept. of Physiology and the Cardiovascular Institute, Loyola University Chicago, Stritch School of Medicine, 2160 South First Ave., Maywood, IL 60153, USA.

	Abstract

 
Capacitative Ca²⁺ entry is a recently discovered Ca²⁺ entry pathway that is activated on depletion of intracellular Ca²⁺ stores, providing an avenue for store refilling. Despite recent progress in elucidating the capacitative Ca²⁺ entry pathway, the mysteries of its molecular identity, its biophysical properties, and the store depletion signal remain.

	Introduction

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
Intracellular Ca²⁺ regulation is an intensely studied field in physiology due to the ubiquitous nature of Ca²⁺ and its prominence as a signaling molecule. Because changes, small or large, in the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) can alter a tremendous number of cellular processes, a complete understanding of the regulatory subtleties is essential. A component of this regulation is the capacitative Ca²⁺ entry pathway that provides for a Ca²⁺ influx into the cytoplasm in response to a loss of Ca²⁺ from intracellular Ca²⁺ storage compartments (for review, see Refs. 1, 12).

	Capacitative Ca2+ entry

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
Many cells rely on intracellular stores of Ca²⁺, typically a specialized subcompartment of the endoplasmic reticulum, to promote specific signaling pathways. Release of Ca²⁺ into the cytoplasm from an intracellular storage site provides a means to elevate the [Ca²⁺]_i at discrete subcellular locations or in a spatially uniform pattern throughout the interior of even very large cells. In contrast, Ca²⁺ entry from the extracellular environment would yield pronounced gradients, with the concentration being highest near the plasma membrane. Both routes, release and entry, can be utilized to dictate Ca²⁺ levels within specific domains of the cell. Most nonexcitable cells are dependent on inositol 1,4,5-trisphosphate (IP₃)-sensitive intracellular stores to increase the [Ca²⁺]_i in response to physiological stimuli. As an example, a typical ATP-induced [Ca²⁺]_i transient in a single, cultured vascular endothelial cell is shown in Fig. 1A. In the presence of extracellular Ca²⁺, the transient is characterized by a rapid upstroke, followed by a gradual decline to a plateau level of elevated Ca²⁺ (Fig. 1A). However, after removal of extracellular Ca²⁺, the plateau phase of elevated Ca²⁺ is abolished (Fig. 1B). Figure 1 demonstrates the combined effects of agonist stimulation triggering Ca²⁺ release from internal Ca²⁺ stores (the rapid upstroke of [Ca²⁺]_i) and extracellular Ca²⁺ entry to maintain the elevated plateau phase of Ca²⁺. The experiment performed in Ca²⁺-free conditions shows that the increase in the intracellular Ca²⁺ signal can be reasonably short lived (Fig. 1B). To achieve this return to baseline on a fast time scale, cells use an endoplasmic reticulum Ca²⁺-adenosine 5'-triphosphatase (ATPase) to recycle Ca²⁺ back into the stores, making it available for subsequent release. In addition, cells also utilize the plasma membrane to transport Ca²⁺ out of the cell and decrease [Ca²⁺]_i (via Na⁺/Ca²⁺ exchange and plasma membrane Ca²⁺-ATPase). This makes the reliance on an intracellular store to generate transient increases in [Ca²⁺]_i problematic because the amount of Ca²⁺ within the stores is finite compared with the extracellular environment. Indeed, for every [Ca²⁺]_i transient generated by release from intracellular stores, a fraction of that load is lost to the extracellular environment.

View larger version (18K): [in this window] [in a new window]   FIGURE 1. Capacitative Ca2+ entry signals. Prolonged stimulation of a single vascular endothelial cell (CPAE cell; cell line derived from calf pulmonary artery endothelium) with ATP in the presence (A) or absence (B) of 2 mM extracellular Ca2+ ([Ca2+]o). Cytoplasmic Ca2+ concentration ([Ca2+]i) was measured with the Ca2+-sensitive dye indo 1. Sustained Ca2+ influx that occurred in the presence of extracellular Ca2+ (A) is thought to be due to activation of capacitative Ca2+ entry. C: standard protocol to activate capacitative Ca2+ entry consisted of Ca2+ store depletion with thapsigargin in the absence of extracellular Ca2+. Ca2+ was returned to the surrounding bath solution, and subsequent rise in [Ca2+]i (overshoot) was due to capacitative Ca2+ entry. D: subcellular [Ca2+]i gradients during capacitative Ca2+ entry were measured using confocal laser scanning microscopy in a fluo 3-loaded, thapsigargin-treated cell. At left, a–c mark locations in cell.

Capacitative Ca²⁺ entry, first proposed by Putney (11) and recently reviewed in great and thorough detail (12), is a term based on its analogy to a capacitor in an electrical circuit. The pathway is characterized by the fact that charged or full intracellular stores prevent Ca²⁺ current flow through this pathway, whereas discharged or empty stores promote Ca²⁺ flux into the cytoplasm. Evidence is accumulating that these capacitative transport pathways may be a family of channels, on the basis of the various kinetics reported for Ca²⁺ influx (for review, see Ref. 3). These entry channels do not conform to the typical characteristics of other well-recognized Ca²⁺ influx pathways, such as voltage-operated channels, second messenger-operated channels, or receptor-operated channels (for review, see Ref. 4). This unique capacitative Ca²⁺ entry family of influx pathways has been demonstrated in numerous cell types, including endothelial cells, exocrine acinar cells, lymphocytes, oocytes, and hepatocytes to name a few. In general, excitable cells do not appear to generate a "traditional" capacitative Ca²⁺ entry. This may be because these cells generate significant voltage-dependent Ca²⁺ influx across the plasma membrane during excitation, which may make the sustaining action of the capacitative Ca²⁺ entry redundant. In addition, most excitable cells are much less dependent on IP₃-sensitive stores to increase the [Ca²⁺]_i. That being said, some smooth muscle cells, chromaffin cells, and adrenal glomerulosa cells have been shown to generate capacitative Ca²⁺ entry, and this may be attributed to their partial reliance on IP₃-sensitive intracellular stores.

	Evidence for store dependence

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
Although many aspects of capacitative Ca²⁺ entry remain unknown or controversial, the store-dependent generation of the plasma membrane Ca²⁺ influx appears to be certain and well documented. The first direct experimental proof of the capacitative Ca²⁺ entry model was demonstrated by Hallam et al. (5). They determined that depletion of the intracellular stores activated Ca²⁺ entry by a mechanism independent of receptor occupation or inositol phosphates. Depletion of the intracellular stores by repetitive agonist stimulation in a Ca²⁺-free environment triggered a large influx of Ca²⁺ when the ion was returned to the extracellular environment. This large Ca²⁺ influx or "overshoot" is now the characteristic trademark of capacitative Ca²⁺ entry. This influx pathway can also be activated by inhibition of the sarcoplasmic-endoplasmic reticulum Ca²⁺-ATPase pump using thapsigargin, cyclopiazonic acid, or 2,5-di-tert-butyl-1,4-benzohydroquinone. These inhibitors block the sequestration of Ca²⁺, thereby promoting the depletion of the stores and triggering capacitative Ca²⁺ entry. Figure 1C illustrates a typical protocol for depleting the intracellular stores of Ca²⁺ with thapsigargin in a Ca²⁺-free extracellular solution. The subsequent readdition of Ca²⁺ to the surrounding bath induces a large increase in [Ca²⁺]_i (overshoot), indicative of capacitative Ca²⁺ entry. Prolonged incubation or perfusion of cells in Ca²⁺-free solution alone will also trigger capacitative Ca²⁺ entry, following the return of extracellular Ca²⁺. This demonstrates that a rise in intracellular Ca²⁺ is not a prerequisite to the activation of this pathway in cultured vascular endothelial cells.

Regardless of the mechanism used to generate the capacitative Ca²⁺ influx in these cells, spatially resolved measurements show distinct cellular gradients (Fig. 1D). Activation of the capacitative pathway causes the [Ca²⁺]_i to rise faster and to higher levels in the cell periphery compared with the perinuclear region or the nucleus (Fig. 1D). The most likely explanation for these differences in the subcellular capacitative Ca²⁺ entry transients is regional differences in the membrane surface area-to-volume ratio. The thickness of the cultured vascular endothelial cell dramatically decreases from the nuclear region toward the cell's periphery. Thus the surface-to-volume ratio is highest in the periphery and decreases toward the nucleus. As a result, during Ca²⁺ entry across the plasma membrane, [Ca²⁺]_i rose faster and to higher levels in the periphery (Fig. 1Da). In contrast, the Ca²⁺ signal was slower and the initial overshoot smaller close to or in the cell nucleus (Fig. 1D, b and c, respectively). These marked [Ca²⁺]_i gradients during capacitative entry slowly disappeared as [Ca²⁺]_i relaxed to a sustained plateau level in the continuous presence of extracellular Ca²⁺. Together, this influx pathway can be activated in the absence of agonist, IP₃, or elevation of [Ca²⁺]_i. Therefore, depletion of the intracellular stores appears to be the sole requirement for stimulation of the mechanism inducing capacitative Ca²⁺ entry.

	How is the intracellular store status detected and transmitted to the plasma membrane influx channel?

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
In contrast to the relative certainty associated with the store-dependent control of the capacitative Ca²⁺ entry channel, the means by which the level of Ca²⁺ in the stores is monitored and communicated to the plasma membrane is very unclear. Any model of capacitative Ca²⁺ entry requires that the intracellular compartment communicates the status of its filling to the plasma membrane influx channels. This particular aspect of the process has received considerable attention. To date, no clear mechanism has been established and very little precedence exists for the biological monitoring of an intracellular storage compartment. However, there are a number of noteworthy theories about capacitative Ca²⁺ entry that are in various stages of development. One of the original suggestions held that depleted storage compartments release a low-molecular-weight factor or diffusible signal, the so-called "Ca²⁺ influx factor," into the cytoplasm (Fig. 2A). This factor was described as being a phosphorylated compound with a molecular mass of <500 Da (13). Evidence exists to suggest that this factor is responsible for activating the Ca²⁺ influx at the plasma membrane. However, other diffusible signals have received attention, including inositol 1,3,4,5-tetrakisphosphate (IP₄), guanosine 3',5'-cyclic monophosphate, and metabolites of the cytochrome P-450 system. The activation of a tyrosine kinase is also suggested to occur in a parallel fashion with store Ca²⁺ depletion. Indeed, it has been demonstrated that depletion-induced Ca²⁺ influx is associated with tyrosine phosphorylation in endothelial cells. On the basis of the known influence of tyrosine phosphorylation on many different Ca²⁺-transport pathways, this is an attractive hypothesis. However, a consensus on the factors or molecules involved in capacitative Ca²⁺ entry has not been reached (for further references to this topic, see Ref. 12).

View larger version (12K): [in this window] [in a new window]   FIGURE 2. Hypothetical models for capacitative Ca2+ entry signaling between intracellular Ca2+ stores and plasma membrane. A: diffusible factor model is based on activation and/or production of some messenger molecule following store depletion, and this diffusible messenger in turn activates the capacitative Ca2+ entry pathway. CCE, capacitative Ca2+ entry channel. B: conformational coupling model involves direct protein-protein interaction between inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) in the endoplasmic reticulum (ER) membrane and capacitative Ca2+ channel in the plasma membrane. C: channel insertion model states that, on depletion of intracellular stores, vesicles containing the capacitative channel are exocytotically inserted in the plasma membrane of cell. These models should not be viewed as mutually exclusive; rather, aspects of each model could play a role in capacitative Ca2+ entry.

Of course, this model assumes that the required capacitative Ca²⁺ entry channels tonically reside at the plasma membrane. However, Fasolato et al. (4) and Somasundaram et al. (15) have proposed that the channels reside in intracellular vesicles and are inserted exocytotically in response to the appropriate signal (Fig. 2C). Downregulation of capacitative Ca²⁺ entry could occur by endocytotic recycling of the capacitative Ca²⁺ entry pathways from the plasma membrane. This channel insertion process is similar to other well-characterized channel insertion mechanisms, including the insulin-responsive glucose transporter, the antidiuretic hormone-responsive water channel, the urinary bladder H⁺-ATPase, and the cystic fibrosis transmembrane conductance regulator Cl^– channel. A significant body of literature lends conditional support for and against all the various capacitative Ca²⁺ entry theories listed above; however, to date, clear and decisive evidence remains elusive.

	What is the influx pathway?

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
The specific channel or transporter that allows for capacitative Ca²⁺ entry remains a mystery. Capacitative currents, however, have been measured electrophysiologically, with Hoth and Penner (7) being the first to demonstrate a Ca²⁺ current, in mast cells, associated with store depletion. They termed this current a Ca²⁺ release-activated Ca²⁺ current (I_CRAC), to distinguish it from other plasma membrane Ca²⁺ influx pathways. The CRAC channel is likely to be a subset of the capacitative Ca²⁺ entry channels. I_CRAC is characterized by inward rectification, high Ca²⁺ selectivity, inhibition by intracellular Ca²⁺, and a very low unitary conductance (~0.02 pS). Other studies have suggested that IP₃, IP₄, Ca²⁺, or ATP may directly activate capacitative Ca²⁺ entry channels in different cell types. The conductance of these channels, however, is much larger than the original I_CRAC (ranging from 2 to 20 pS; for review, see Ref. 3) and may represent other members belonging to the family of capacitative Ca²⁺ channels. I_CRAC is frequently used as a synonym for capacitative Ca²⁺ entry, even in studies in which the nature of the influx pathway is not unequivocally established. Because of its well-defined electrophysiological characteristics, however, the terminology I_CRAC should be restricted to store-operated Ca²⁺ currents with the aforementioned properties.

Although the actual channel responsible for these currents has not been identified, there is considerable interest in the Drosophila TRP and TRPL proteins and their mammalian homologues. These proteins are involved in Drosophila phototransduction and display characteristics similar to capacitative Ca²⁺ entry. Another channel protein with regard to the study of capacitative Ca²⁺ entry that is receiving attention is the IP₃ receptor. This protein is expressed as three different isoforms (types 1, 2, and 3) and has been shown in some cell types to be localized to the plasma membrane. It has been suggested that an isoform of the IP₃ receptor could be the capacitative Ca²⁺ entry channel, based on receptor expression studies in Xenopus oocytes (for review, see Ref. 12). Putney (12) has speculated that the type 3 IP₃ receptor may be the capacitative Ca²⁺ entry channel on the basis of its electrophysiological characteristics. However, cultured vascular endothelial cells (e.g., CPAE cells, cell line derived from calf pulmonary artery endothelium) generate a capacitative Ca²⁺ entry transient but fail to express the type 3 IP₃ receptor, based on reverse transcriptase-polymerase chain reaction experiments in our laboratory. Through the combined use of molecular biology and electrophysiological techniques, the identification and characterization of the channel should be imminent. This information will be necessary to efficiently determine the precise signaling mechanisms involved in the activation and regulation of this unique Ca²⁺ influx pathway.

	Interaction of capacitative Ca2+ entry with cytoskeletal microfilaments

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
Our laboratory has focused on the dynamic nature of intracellular Ca²⁺ signaling, including the refilling of intracellular Ca²⁺ stores (2), and the activation/regulation of capacitative Ca²⁺ entry (6). We have specifically investigated the cellular microfilament network and whether or not it is a requirement for capacitative Ca²⁺ entry in endothelial cells. This approach is based on our increasing understanding of the roles of various cytoskeletal elements in intracellular communication as well as the possibility that the microfilaments may serve as a structural or communication link between the intracellular stores and the plasma membrane influx pathway (for review, see Ref. 1).

Because the microfilament network (Fig. 3A) is a dynamic structure, inhibition of new microfilament formation with cytochalasin D leads to the complete degradation of this network (Fig. 3B) and significant alteration of the gross morphology of the cell. After cytochalasin D treatment, the endothelial cell was able to generate a typical ATP-induced [Ca²⁺]_i transient (Fig. 3C), demonstrating that IP₃-dependent release of Ca²⁺ remained intact. However, after thapsigargin application to deplete the intracellular stores, the capacitative Ca²⁺ entry transient was almost completely abolished (Fig. 3C) compared with control (Fig. 3D). Because IP₃ activation of the IP₃ receptor was functional following microfilament disruption, we speculate that a conformational coupling, rather than a diffusible factor, is the more likely model to describe activation of capacitative Ca²⁺ entry in this cell type. However, the cytoskeleton is known to guide exocytotic/endocytotic vesicle trafficking, thereby lending conditional support for the channel insertion hypothesis as well.

View larger version (55K): [in this window] [in a new window]   FIGURE 3. Effect of cytochalasin D on capacitative Ca2+ entry. Confocal images of fluorescein isothiocyanate-phalloidin-stained actin microfilaments in a control cell (A) and after preincubation with cytochalasin D (B). Scale bar: 20 µm. After disruption of actin microfilaments and depletion of intracellular stores, influx of Ca2+ due to capacitative Ca2+ entry activation was almost completely abolished (C) compared with control (D). Dashed line indicates prior treatment with thapsigargin to deplete the Ca2+ stores. [Reproduced and altered from Holda and Blatter (6) with permission.]

Despite some controversy on the interpretation of results with cytochalasin D, these studies demonstrated unequivocally that spatial organization is essential for Ca²⁺ signaling in general and, in particular, capacitative Ca²⁺ entry. This is consistent with recent evidence (10) suggesting that store depletion activates Ca²⁺ entry in a spatially restricted fashion, i.e., Ca²⁺ influx is restricted to membrane regions colocalized with Ca²⁺ stores that have been selectively depleted. From these experiments, it is apparent that the ultrastructural arrangement of the two membranes involved in this signaling pathway is of crucial importance. An even higher level of complexity, in regard to the spatial organization of capacitative Ca²⁺ entry, can be encountered in polarized cell types. In some epithelial cells, capacitative Ca²⁺ entry appears to be restricted to the basolateral membrane. Mogami et al. (9), for example, recently demonstrated that in pancreatic acinar cells Ca²⁺ entry through a basolateral membrane patch was able to recharge Ca²⁺ stores located close to the apical membrane. The authors could not detect any discernible changes in [Ca²⁺]_i during the refilling period. They suggested that Ca²⁺ was rapidly sequestered by Ca²⁺ stores at the site of entry and was subsequently transported through the endoplasmic reticulum network to release sites located in the cell's apical pole. Thus activation of the capacitative Ca²⁺ entry pathway, Ca²⁺ sequestration into the intracellular stores, and the possible subsequent redistribution within the endoplasmic reticulum network are dependent on the subcellular microarchitecture of the membrane, the cytoskeleton, and Ca²⁺ transport proteins involved in this process.

	Outlook for the future

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 
Recent findings have provided increasing evidence that the Ca²⁺ influx due to activation of capacitative Ca²⁺ entry may be important in many cell signaling functions while promoting the refilling of the intracellular Ca²⁺ stores. Nonetheless, this entry pathway remains enigmatic in many aspects of its regulation and function, despite enormous research progress that has uncovered many tantalizing facets of this Ca²⁺ signaling pathway. Crucial issues that remain to be resolved relate to its molecular identity, its biophysical properties, and the identification of the store depletion signal. Research on capacitative Ca²⁺ entry has progressed rapidly. We therefore have great optimism that the near future will shed light on some of these unsolved mysteries.

	Acknowledgments

 
We thank the late Christine E. Rechenmacher, whose expertise and technical help have made this work possible. We thank Drs. Stephen L. Lipsius and Fredy Cifuentes, as well as Jens Kockskämper and Katherine A. Sheehan, for critical reading of the manuscript.

Financial support was provided by the National Institutes of Health, American Heart Association (National Center), Arthur J. Schmitt Foundation, Falk Foundation, and the Deutsche Forschungsgemeinschaft.

L. A. Blatter is an Established Investigator of the American Heart Association.

	References

Top Introduction Capacitative Ca2+ entry Evidence for store dependence How is the intracellular... What is the influx... Interaction of capacitative Ca2+... Outlook for the future References

 

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