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Kozak JA, Putney JW Jr., editors. Calcium Entry Channels in Non-Excitable Cells. Boca Raton (FL): CRC Press/Taylor & Francis; 2018. doi: 10.1201/9781315152592-16

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Calcium Entry Channels in Non-Excitable Cells.

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Chapter 16 Pharmacology of Store-Operated Calcium Entry Channels

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16.1. Introduction

In general, calcium signaling in non-excitable cells is primarily initiated by the activation of surface membrane receptors coupled to phospholipase C (PLC) and stimulates a calcium signaling process that is complex both spatially and temporally, involving the interplay of calcium channels and calcium pumps [1]. Receptor activation of PLC leads to a breakdown of phosphatidylinositol 4,5-bisphosphate in the plasma membrane and production of diacylglycerol and inositol 1,4,5-trisphosphate (IP3) [2]. Fundamentally, receptor activation results in a biphasic process of calcium mobilization composed of the release of intracellular calcium ions from an intracellular organelle, which is coupled to and activates the entry of calcium ions across the plasma membrane of the cell. This second phase of calcium entry is known as store-operated calcium entry (SOCE).

Our ability to identify and define underlying calcium signaling processes and mechanisms is greatly facilitated and influenced by two chief experimental approaches to monitor and characterize the mobilization and movement of Ca2+ ions. Fluorescence-based techniques using calcium-sensitive ion probes provide the ability to measure calcium signals with high temporal and spatial resolution, and simultaneously in multiple cells. However, the measured “fluorescent calcium signal” is the result of multiple processes involving calcium pumps and calcium channels that contribute to a steady-state flux of Ca2+ ions. To identify and discern specific calcium signaling pathways using this technique, it has been very important to employ pharmacological manipulations that help define, or rule out, specific mechanisms. As will be described later, these approaches can help define the underlying calcium entry process as SOCE or non-SOCE, and the potential involvement of Orai and canonical transient receptor potential (TRPC) family proteins.

The other major and complementary technique for defining calcium signaling processes involves the electrophysiological measurement of ion movement. Importantly, this technique can define and distinguish the biophysical properties of underlying calcium channel activities. In concert with pharmacological manipulations, this technique can be used to identify PLC-activated SOCE ion currents either as ICRAC or ISOC and distinguish this from the PLC-activated and non-SOCE ion current IARC (see Chapters 1 and 11).

Much is known about the regulation of intracellular Ca2+ stores by IP3 [3] and the nature of the SOCE process [4–6]. Discoveries within the past decade have helped identify the molecular players underlying PLC-coupled Ca2+ entry, the Ca2+ sensors STIM1 and STIM2, and the SOCE channel subunit proteins Orai1, Orai2, and Orai3 [7]. Indeed, one can describe three types of channels, ICRAC, ISOC, and IARC. ICRAC represents the most extensively characterized store-operated channel and is composed of the pore-forming subunit Orai1, Orai2, or Orai3. ISOC is characterized as a less Ca2+-selective SOCE channel compared to ICRAC that, in addition to the Orai subunit, combines in an incompletely understood manner with TRPC family members (see Chapter 10). As mentioned earlier, there is also a non-store-operated current, IARC, which is gated by arachidonic acid and involves Orai1, Orai3, and STIM1. Since IARC and ICRAC are composed of Orai subunits, they share some similar properties, yet it is possible to clearly distinguish these calcium entry pathways by both biophysical and pharmacological techniques. ICRAC is a small, strongly inwardly rectifying current activated by Ca2+ store depletion and inhibited by the drug 2-APB (discussed later). IARC is a similarly small and strongly inwardly rectifying current, activated by a ligand (not by store depletion), has a different pH sensitivity, exhibits reduced or lacks fast Ca2+-dependent inactivation (CDI), does not rapidly depotentiate, and is not inhibited by 2-APB. In addition, Orai1 was recently discovered to be expressed as two isoforms due to alternative translation initiation, Orai1α (long) and Orai1β (short) [8]. Channels composed of either Orai1α and Orai1β can associate with STIM1 and form CRAC or SOC channels. However, only Orai1α, and not Orai1β, undergoes CDI, and only Orai1α appears to form channels underlying IARC [9] (see Chapter 11).

Today, our ability to pharmacologically dissect and manipulate the SOCE calcium signaling pathway remains a readily accessible way to understand receptor-regulated calcium signaling in a wide variety of biological systems. This is particularly useful in systems where molecular biological strategies are difficult to employ. However, it always remains a challenge to ensure these pharmacological approaches provide some degree of specificity and control.

16.2. PLC Activation and Store-Operated Calcium Channels

As mentioned earlier, PLC activation results in a biphasic process of calcium mobilization. The first phase of calcium release is often attributable to IP3, which acts by binding to a specific receptor on the endoplasmic reticulum (ER) [10]. The second phase of calcium entry is most commonly attributed to SOCE. This process is not regulated by direct actions of IP3 on the plasma membrane but by a process of retrograde signaling, whereby the depletion of an intracellular calcium storage organelle produces a signal for calcium ion entry across the plasma membrane [4,11] (see Chapter 3). This biphasic signaling process is best illustrated under conditions where the receptors are maximally activated.

However, under more physiological conditions of receptor activation, the resulting calcium signals are complex both spatially and temporally. Rather that the simple, bimodal response observed with high agonist concentrations, activation of PLC-coupled receptors with lower, more physiological concentrations of agonists results in a complex, repetitive cycling of [Ca2+]i, known as [Ca2+]i oscillations [12,13]. These calcium oscillations depend upon complex mechanisms of regenerative intracellular signaling events, either at the level of PLC activity or the IP3 receptor calcium release channel. These oscillatory calcium events arise from a process that depends on an interrelationship between calcium release and calcium entry, and Ca entry is necessary to sustain this process for extended periods of receptor activation (discussed also in Chapter 5).

There is some discussion that the Ca entry process triggered under more physiological conditions of PLC activation may differ from that activated under maximal receptor activation. The suggestion being that PLC activation can regulate a separate Ca2+ entry pathway in addition to SOCE [14]. To discern the underlying route for receptor-mediated Ca2+ entry, it has been critical to employ molecular and pharmacological interventions. This provides a means to identify SOCE and distinguish it from pathways that do not involve SOCE [13,15].

16.3. Pharmacological Activation of Store-Operated Channels

The single initial signal for the activation of SOCE and ICRAC is the depletion of intracellular Ca2+ stores located in the ER. PLC-coupled receptors initiate this process through the production of IP3. However, this process represents an uncontrolled approach for manipulating SOCE since (1) the magnitude and kinetics of PLC activation may vary and (2) PLC may activate pathways that are unrelated or interfere with SOCE.

A preferable strategy is to employ pharmacological approaches that target the depletion of ER Ca2+ pools directly to activate SOCE, independent of activating PLC-coupled receptors. In general, there are several ways in which this can be achieved: (1) blockade of SERCA pumps, (2) use of a Ca2+ ionophore, (3) direct activation of the IP3 receptor, and (4) “passive depletion” of ER Ca2+ pools (usually by patch-clamp technique; see Chapter 1).

16.3.1. SERCA Pump Inhibition

The ER serves as a critical Ca2+ buffer with SERCA Ca2+ ATPase pumps that can rapidly sequester Ca2+ ions from the cell cytoplasm. This activity serves to prevent untoward changes in [Ca2+]i and replenish intracellular Ca2+ stores following PLC activation. Even in unstimulated cells considered “at rest,” Ca2+ ions are continually cycling across the ER membrane with the actions of SERCA pumps sequestering Ca2+ balanced against a poorly defined “Ca2+ leak” process out of the ER. However, by inhibiting this SERCA Ca2+ATPase activity, the prevailing “Ca2+ leak” process will result in depletion of ER Ca2+ stores and full activation of SOCE [16] (see Chapter 1).

There is a selection of membrane permeant SERCA inhibitors available that provide a noninvasive technique for manipulating ER Ca2+ pools in intact cells. These include thapsigargin, cyclopiazonic acid (CPA), and tBHQ [17]. Historically, it was the discovery of thapsigargin that first provided the clearest demonstration and important validation of the SOCE pathway. Importantly, treatment of cells with these inhibitors made it possible to deplete the IP3-sensitive Ca2+ stores and activate SOCE without formation of any inositol phosphates associated with agonist activation [18,19]. Of the three SERCA inhibitors, only the more water-soluble CPA can be readily washed out of cells. This property of CPA provides the ability to partially deplete intracellular Ca2+ stores and thus partially activate SOCE [20,21]. An example of the use of thapsigargin to determine the effects of a pharmacological inhibitor on the size of the intracellular Ca2+ pool and the magnitude of SOCE is illustrated in Figure 16.1.

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Figure 16.1

Effect of a SOCE inhibitor on the thapsigargin-induced biphasic calcium signaling using the calcium readdition protocol in fura-5F-loaded HEK 293 cells. HEK 293 attached to glass cover slips were loaded with the calcium indicator fura-5F, and cytoplasmic (more...)

16.3.2. Ca2+ Ionophores

The use of Ca2+ ionophores provides an alternative strategy for depleting intracellular Ca2+ from the ER and activating SOCE. A23187 [22] and ionomycin [23] are lipid-soluble carboxylic acid antibiotics that transport divalent but not monovalent cations. In general, Ca2+ ionophores have proven useful in transporting Ca2+ ions across a variety of membranes and manipulating intracellular Ca2+ pools in intact cells. Experimentally, ionomycin performs better and is more selective than A23187 in transporting Ca2+ ions [23].

However, the actions of ionomycin on manipulating Ca2+ movements are complex and concentration dependent. At concentrations ∼10 μM, ionomycin increases the permeability of Ca2+ ions across all cell membranes. However, at concentrations <1 μM, ionomycin appears to selectively partition into intracellular membranes and release intracellular Ca2+ stores without greatly increasing the permeability of the plasma membrane to extracellular calcium [24]. At low concentrations, ionomycin can enhance Ca2+ influx by stimulating store-regulated cation entry and not by a direct action at the plasma membrane [25]. Under these conditions, this effect of low concentrations of ionomycin can be used to activate SOCE (see Chapter 5).

16.3.3. Activation of IP3 Receptors

Monitoring currents associated with SOCE is achieved using the whole-cell patch-clamp technique that, in this mode, allows the intracellular milieu to be modified directly with the internal patch pipette solution. Thus, rather than relying on the external application of SERCA pump inhibitors to activate SOCE channels, the intracellular Ca2+ store depletion can be achieved by addition of metabolizable or nonmetabolizable analogs of IP3 (in conjunction with EGTA or BAPTA) [26] directly to the internal pipette solution (see Chapter 1).

16.3.4. Passive Depletion of ER Ca2+ Pools

As mentioned earlier, the use of the whole-cell patch-clamp technique allows the intracellular milieu to be modified directly with the internal patch pipette solution. By simply breaking into cells with a patch pipette solution containing a high concentration of the Ca2+ chelators BAPTA or EGTA, the intracellular ER Ca2+ stores are gradually emptied. This “passive depletion” of Ca2+ results in ICRAC activation that is equivalent to that activated by IP3 or thapsigargin; however, this passive process is slow to develop fully (in the order of minutes). This is a technique that can be used in conjunction with IP3 to facilitate a rapid and maximal activation of ICRAC [27]. The slow onset of ICRAC with passive depletion can be of experimental advantage as it provides sufficient time to obtain control, baseline current measurements before significant store depletion is achieved (discussed in Chapter 1).

16.3.5. Membrane Potential

By definition, activation of Ca2+ entry in non-excitable cells results from IP3-mediated Ca2+ store depletion rather than through voltage activation [1]. However, SOCE is an electrogenic process and can be influenced by the concentration gradient of Ca2+ ions and membrane potential across the plasma membrane. Thus, less calcium enters upon plasma membrane depolarization, and hyperpolarization will promote calcium influx [28] (see Figure 1.1). Thus, it is important to control the effects of membrane potential when considering the specificity of a pharmacological agent to modulate a Ca2+ entry signal. This may especially be important with pharmacological manipulations that inhibit Ca2+ entry where toxic insults to a cell might damage the plasma membrane and cause depolarization. Should this be a concern, the effects of pharmacological agents can be studied using the patch-clamp technique where fluxes of calcium ions across the membrane are measured and membrane potential controlled (i.e., voltage clamp).

16.4. Pharmacological Inhibition of Store-Operated Channels

While pharmacological activation of SOCE with SERCA pump inhibitors such as thapsigargin was crucial for developing our understanding of SOCE in intact cells, our ability to manipulate SOCE channels directly and inhibit them with any degree of specificity has historically been rather limited. However, the progress made in identifying the molecular players underlying the SOCE pathway has provided an opportunity to screen for and develop drugs that can modulate channel activity or act directly at the pore of the channel. In this section, we summarize a range of pharmacological agents that target SOCE channel inhibitors and are commercially available.

16.4.1. Lanthanides

The lanthanides La3+ and Gd3+ have been the most widely employed tools for blocking SOCE [29]. Interestingly, lanthanides were initially used to block both Ca2+ entry and Ca2+ efflux via the plasma membrane Ca2+ATPase (PMCA) [30]. These effects, on entry and efflux, however, can be dissociated due to differential sensitivities of the processes to lanthanides. At low concentrations, lanthanides can block SOCE (<1 μM) [31]. With identification of Orai, studies suggest that lanthanides act by blocking access of Ca2+ ions to the selectivity filter and pore, a likely target being acidic residues in loop I–II [32].

At concentrations above 100 μM, lanthanides begin to block PMCA activity [13,30] and appear to block completely at concentrations at or above 1 mM. The cytoplasm then appears isolated or “insulated” from the extracellular space. Under these conditions, this “gadolinium insulation” is blocking both the entry and efflux of Ca2+ ions and presents an opportunity to investigate complex intracellular calcium signaling events independently of contributions made by constituents in the extracellular space [13].

16.4.2. 2-APB (2-Aminoethyldiphenyl Borate)

2-APB has broadly been used as an inhibitor for SOCE and ICRAC. This compound was originally described as a noncompetitive inhibitor of the IP3 receptor. The effects of 2-APB are far more complex, while it has been found to modulate many other ion channels [7,33–36]. The effects of 2-APB on SOCE and ICRAC appear to be extracellular and act independently of IP3 receptor inhibition [37,38]. However, by careful application, 2-APB can still be useful in distinguishing between SOCE and other channels, particularly in overexpression systems and interrogating the actions of STIM1 and the role of Orai isoforms in the activation of SOCE and ICRAC.

2-APB has a dose-dependent bimodal effect on SOCE. At low concentrations (<5 μM), SOCE is enhanced, then transient enhancement and inhibition occurs at doses >20 μM [34,39,40]. At high doses, 2-APB was observed to inhibit STIM1 puncta formation at the plasma membrane, suggesting that current inhibition involved disruption of coupling to and activation of Orai channels [34,41]. However, this simple mechanism does not explain the full spectrum of 2-APB effects. For example, when overexpressing STIM1 and Orai1 together in HEK cells, 2-APB is less effective in inhibiting STIM1 puncta formation yet retains its potency for inhibiting SOCE and ICRAC [34].

2-APB differs in its actions against the three Orai isoforms; as discussed earlier, it has a biphasic effect on Orai1 channels (and most native CRAC channels), a weaker effect against Orai2 channels, whereas it directly and potently activates Orai3 channels [34,40,41].

Two dimeric derivatives of 2-APB, DPB162-AE and DPB163-AE, were identified in a screen of chemical analogs with more potency in inhibiting SOCE and ICRAC and with considerable specificity for action on STIM1 and Orai1-dependent SOCE [42,43]. While DPB163-AE retained a bimodal effect on SOCE with dose-dependent potentiation and inhibition, DPB162-AE was shown to only inhibit SOCE [44].

16.4.3. ML-9

ML-9, an inhibitor of myosin light chain kinase (MLCK), was discovered to inhibit SOCE and thus suggested a possible role for MLCK in the mechanism of SOCE activation [45]. The mechanism of action of ML-9 remains unclear but appears to be centered on disrupting the coupling of STIM1 and Orai1. ML-9 was found to disperse thapsigargin-induced STIM1 puncta, an event that appeared to precede the loss of SOCE. However, these effects of ML-9 on SOCE were independent of MLCK. An alternative MLCK inhibitor, wortmannin (20 μM), had no effect on SOCE, and the effects of ML-9 were unaffected by the knockdown of MLCK. ML-9 has limited application in cells overexpressing STIM1 and/or Orai1: overexpression of STIM1 reduces the effect of ML-9 on SOCE, and co-overexpression of STIM1 with Orai1 renders ML-9 ineffective.

16.4.4. BTP2 (YM-58483)

BTP2 is a member of a family of bis(trifluoromethyl)pyrazoles that have been shown to inhibit thapsigargin-induced SOCE and ICRAC activation [46–48]. Experimentally, BTP2 proves a more potent and irreversible inhibitor of SOCE if cells are exposed to the drug for many hours prior to cell activation. While this is inconvenient from a practical standpoint, it does suggest that the mechanism of action of BTP2 is indirect and not likely a channel pore blockade. The specificity of BTP2 for directly inhibiting SOCE has also been challenged on the basis that this compound can activate TRPM4 [47]. It is suggested that activation of TRPM4, a Na-permeable channel, can depolarize the plasma membrane potential. As discussed earlier, membrane depolarization will reduce the driving force for Ca2+ entry and thus indirectly also SOCE.

16.4.5. Synta 66

Synta 66 appears to be a potent and highly selective inhibitor of SOCE and ICRAC activation [49,50]. Synta 66 does share some of the properties of the structurally related BTP2: it is a slow and irreversible inhibitor, requiring cells to be exposed to the compound for long periods before calcium signaling is activated. As with BTP2, this would suggest that Synta 66 is not targeting the channel pore. However, Synta 66 has no effect on STIM1 puncta formation [51] and likely acts downstream of STIM1 oligomerization.

16.4.6. GSK-7975A and GSK-5503A

GSK-7975A and GSK-5503A are two pyrazole derivatives that appear to be highly selective inhibitors of SOCE and ICRAC activation ([52] and Figure 16.1). Somewhat like Synta 66 and BTP2, cells have to be preincubated with these compounds in order for them to be fully effective in blocking Ca2+ entry. However, in this case, cells need only be exposed for a period of minutes rather than hours. Focusing on GSK-7975A, Derler et al. [52] investigated possible mechanisms of inhibition. They concluded that GSK-7975A was acting downstream of STIM1 oligomerization and STIM1/Orai1 interaction and its inhibitory effect is likely due to interference with the ion permeation through the Orai pore. This study also screened the effects of GSK-7975A against a panel of 16 ion channels concluding that this compound retained a high degree of selectivity. A weak inhibitory effect was observed for an L-type (Cav) Ca2+ channel and a more robust inhibition for TRPV6 channels.

16.4.7. RO2959

RO2959 is a potent SOCE and ICRAC inhibitor that blocked an IP3-dependent current in RBL-2H3 mast cells, in CHO cells stably expressing human Orai1 and STIM1 and in human CD4+ T lymphocytes [53]. As with BTP2, Synta 66, and the GSK compounds, cells need to be treated with RO2959 at least 30 min before cell activation. The mechanism of RO2959 inhibition has not been addressed, although the required preincubation period would suggest it is not a pore blocker.

16.4.8. AnCoA4

AnCoA4 is a SOCE inhibitor discovered in a small-molecule microarray screen targeting the SOCE pathway. Instead of using a cell-based screening assay, Sadaghiani et al. [54] identified peptides encompassing Orai1 and STIM1 domains that are important for the gating of CRAC channels, purified, and immobilized them in microarrays. This was used to screen a library of molecules and identify those that interacted with these STIM1/Orai1 domains. In follow-up functional tests, AnCoA4 was found to inhibit thapsigargin-induced SOCE and CRAC channels at concentrations in the low micromolar range. The inhibitory effect of AnCoA4 was more potent when added before cell activation (∼5 μM) when compared to the concentrations required for inhibition after cell activation (20 μM). This suggests that AnCoA4 is more effective when presented to cells before STIM1 starts to interact with Orai1.

16.4.9. SKF96365 and Other Imidazoles

A number of related imidazole compounds are inhibitors of SOCE and include SKF96365, econazole, miconazole, and clotrimazole. The use of these compounds is problematic and certainly not a first choice. While their mechanism of action remains elusive, a chief concern is their lack of specificity for SOCE. Indeed, these compounds have been shown to block voltage-gated Ca2+ channels [55,56], potassium channels [57], and TRP family members [58,59].

16.4.10. Diethylstilbestrol

Diethylstilbestrol (DES) is a synthetic estrogen agonist that has been described as an inhibitor of thapsigargin-induced SOCE and ICRAC [60]. The effect of DES is rapid, requiring no pretreatment, is reversible and exerts its effect rapidly via the extracellular side of the plasma membrane. DES also had no effect on STIM1 clustering and translocation [61]. These characteristics suggest DES may inhibit SOCE at the pore. In terms of selectivity, Zakharov and colleagues demonstrated that DES had no effect on monovalent cation currents that are mediated by TRPM7 channels [60]. However, in earlier studies in smooth muscle cells, it was found that DES inhibited nonselective cation currents and K+ currents [62]. On a cautionary note, a study in A7r5 smooth muscle cells [63] demonstrated that the observed effects of DES on inhibiting the calcium entry process were transient. However, this was not due to a transient inhibition of SOCE itself but rather an off-target effect of DES to promote other Ca2+ transport mechanisms.

16.5. Concluding Remarks

In this short chapter, we have attempted to outline some of the general aspects of pharmacological and experimental manipulation of SOCE, as well as briefly summarizing the effects of reagents that are currently available to the experimentalist. As researchers continue to search for potent and selective agonists and antagonists, the next phase of SOCE pharmacology may well include significant clinical aspects of this widely encountered and physiologically important pathway.

Acknowledgment

Work from the authors’ laboratory was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.

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Gary S. Bird

Signal Transduction Laboratory

National Institute of Environmental Health Sciences

National Institutes of Health

Research Triangle Park, North Carolina

James W. Putney, Jr.

Signal Transduction Laboratory

National Institute of Environmental Health Sciences

National Institutes of Health

Research Triangle Park, North Carolina

© 2017 by Taylor & Francis Group, LLC.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Bookshelf ID: NBK531424PMID: 30299647DOI: 10.1201/9781315152592-16
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