1.1. Introduction

During the past two decades, great advances have been made in the electrophysiological and molecular identification of calcium entry pathways in non-excitable cells. The term “non-excitable” refers to a variety of cell types that are not capable of firing action potentials. Essentially, except for neurons, muscle cells, and some endocrine cells, all other cells in the body are non-excitable. For the most part, they lack the necessary levels of expression of voltage-gated Na⁺ channels (Na_V family) and also voltage-gated Ca²⁺ channels (Ca_V family). Ca²⁺ influx in these cell types is therefore thought to rely on unrelated, voltage-independent channels, such as Orai (CRACM) and TRP family members. In this chapter, we will discuss direct electrophysiological methods used to record the electrical activity of these proteins, focusing on calcium-selective Orai/STIM and TRPV5/TRPV6 channels.

1.2. Characteristics of Calcium Entry in Non-excitable Cells

One of the first non-excitable cell types used to investigate the function of non-voltage-gated Ca²⁺ channels was cells of the immune system [1]. In T lymphocytes and mast cells, store-operated calcium entry is the main pathway providing cytoplasmic calcium elevations necessary for key cellular functions, such as antigenic activation, proliferation, and degranulation. Calcium stores inside the cell that were shown to be important for CRAC channel activation and functions are the endoplasmic reticulum (ER) and mitochondria [2–6].

Direct evidence for calcium entry following store depletion was demonstrated using the now classical calcium readdition protocol in cells loaded with calcium indicator dyes, such as Fura-2. Figure 1.1 shows a calcium imaging experiment in Jurkat T lymphocytes loaded with Fura-2 ratiometric calcium dye. Upon the removal of calcium and the simultaneous addition of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump inhibitor cyclopiazonic acid (CPA) [7], a transient calcium elevation was observed. This is believed to represent the release of ionized calcium from the ER into the cytoplasm (Fura-2 indicator is in the cytoplasm). Calcium release in this case is mediated through a “Ca²⁺ leak” pathway operating in the ER membrane. Normally, SERCA acts to sequester cytoplasmic calcium into the ER, counteracting this outwardly directed calcium leak. When SERCA is blocked by CPA, however, the calcium flux into the cytoplasm due to the leak pathway is no longer counteracted and this is manifested as a calcium elevation. The transient nature of this elevation is likely due to plasma membrane Ca²⁺ ATPase (PMCA), which is not sensitive to CPA and can still expel calcium ions from the cytoplasm.

Figure 1.1

Fura-2 measurement of cytosolic calcium in intact human Jurkat T lymphocytes (a) and murine MIN6 β cells (b).

The basal ER “Ca²⁺ leak” pathway remains an enigma both in terms of its molecular identity and the factors that regulate it. It is thought to participate in determining the ER calcium content (also termed “calcium load”). Over the years several ion channels have been proposed to underlie the ER leak such as the translocon complex (translocation channel), pannexins, TRPP2 (polycystin), Bcl2 anti-apoptotic proteins, and even IP₃R channels functioning in the absence of ligand binding [8–12]. It is presently unclear if Ca²⁺ leak channels are regulated by ER calcium content and cytoplasmic Ca²⁺ or if they are constitutively open. In whole-cell patch-clamp experiments, the leak pathway appears to function throughout the duration of the recording, enabling the prolonged continuous detection of CRAC channel activity with passive store depletion. Almost no information is available on their pharmacology. Basal leak pathways have also been described in the cardiac sarcoplasmic reticulum, and ryanodine receptors have been suggested to participate in basal leak under specific circumstances [10].

The reintroduction of calcium to the bathing solution (in the presence of CPA) results in a large calcium elevation, which represents store-operated calcium entry (SOCE). This process is a direct consequence of emptying the ER calcium store, as this pathway is not active without CPA or thapsigargin application. In lymphocytes, SOCE is usually larger than the ER release transient and also decays more slowly. When extracellular [K⁺] is increased from 4 to 140 mM (Figure 1.1b) calcium increases are drastically diminished. K⁺ elevation moves the potassium Nernst potential from -90 mV to approximately 0 mV, a 90 mV depolarization. This is expected to depolarize the membrane potential of the Jurkat T cell, which is set by the voltage-gated K_V1.3 and calcium-activated K_Ca3.1 channels, as well as the two-pore voltage-independent K⁺ channels [13,14]. Depolarized potentials result in a reduced driving force for Ca²⁺, thereby decreasing Ca²⁺ influx. This in turn reduces K_Ca3.1 currents in a positive feedback loop, causing Ca²⁺ transients to decay faster [1]. Importantly, the shape (time course) of SOCE is set by PMCA activity [6,15–18]. In short, membrane depolarization reduces rather than increases SOCE, demonstrating that in lymphocytes, voltage-gated Ca_V channels are not the underlying calcium influx pathway. Accordingly, the blockade of K_V1.3 in lymphocytes invariably inhibits SOCE and suppresses proliferation, which requires SOCE [19,20]. Similar SOCE-K⁺ channel systems exist in other cell types [21]. Note that the CPA-induced store calcium transient is not affected by the rise in the extracellular K⁺ concentration since it does not depend on the plasma membrane potential. SOCE is not entirely abolished in high K⁺, presumably because the calcium equilibrium potential is well above 0 mV [22]. By contrast, in excitable cells, such as pancreatic β cells, depolarizations caused by increasing [K⁺] result in a substantial Ca²⁺ influx through voltage-gated Ca²⁺ channels of the Ca_V family (Figure 1.1b). In β cells the major Ca_V subtype is the dihydropyridine-sensitive L-type channel, which opens at membrane potentials above -10 mV [23,24].

1.3. CRAC Channels

1.3.6. CRAC Single-Channel Conductance

One of the fundamental characteristics of an ion channel is its conductance. The first recordings of I_CRAC in mast cells and lymphocytes suggested that the conductance of a single CRAC channel is well below the levels that can be resolved by patch clamping as single-channel currents [26,70,91]. The standard approach in cases when single-channel conductance is too small for patch-clamp recording is to use the so-called nonstationary noise analysis (analysis of variance) [92]. Due to the stochastic nature of single-channel opening, a steady-state macroscopic current mediated by a constant number of channels fluctuates with time around its mean value. The nonstationary noise analysis is based on the fact that the magnitude of these fluctuations depends on the amplitude of the single-channel current, the number of channels, and their open probability [92,93]. The relationship between current variance (σ²; averaged squared current fluctuations from its mean) and single-channel current is given by the following equation:

$${\mathrm{\sigma }}^2=iI-\frac{I^2}{N}$$

1.1

where

• I is the mean amplitude of the macroscopic current
• i is the single-channel current
• N is the number of channels

I, i, and N parameters can be used to determine the open probability P_o:

$$P_{\mathrm{o}}=\frac{I}{iN}$$

1.2

Originally, nonstationary noise analysis was used for voltage-gated channels, where current is recorded in response to a voltage step that promotes channels to either open or close, so that the P_o of the channels under investigation would change significantly during that voltage step, preferably by more than 50% [93]. The recorded current traces (at least 100 sweeps are normally required) are averaged to obtain a mean current trace and variance. The calculated variance is then plotted against the mean current and the data points fitted with a parabola (Equation 1.1), which gives unitary channel current i and the number of channels N [92,93].

Although CRAC channels show some voltage dependence due to fast Ca²⁺-dependent inactivation at negative potentials [26,94], it is virtually impossible to record a large enough number of current sweeps in response to voltage steps below -100 mV in one cell due to an I_CRAC drift and rundown. The first attempts of CRAC unitary conductance estimation used traces of I_CRAC development in Jurkat T cells at a constant voltage of -80 mV in a bath solution containing 2 mM Ca²⁺, which was then switched to 110 mM Ca²⁺ [70]. This approach was based on the assumption that the changes in I_CRAC amplitude during current development and its slow inactivation in a solution containing 110 mM Ca²⁺ were due to the changes in CRAC channel P_o. Current variance was calculated from 200 ms episodes taken from every 2 s of continuous recording and plotted against corresponding mean current amplitudes [70]. In these plots, variance showed linear dependence on the current amplitude, which suggested a low P_o of CRAC channels [70] (Figure 1.2). The calculated single-channel current amplitudes were -1.4 fA in 2 mM Ca²⁺ and -3.6 fA in 110 mM Ca²⁺ at -80 mV. The estimated single-channel conductances were 9 and 24 fS, respectively [70].

Figure 1.2

Fluctuation analysis of currents stimulated by thapsigargin in Jurkat T cells.

As discussed earlier, in the absence of Ca²⁺ and Mg²⁺, CRAC channels become permeable to monovalent cations. Replacing physiological (Ca²⁺-containing) bath solutions with divalent cation-free solutions causes a 7–8-fold increase in I_CRAC amplitude followed by current deactivation to about 20%–30% of its peak value within 30–60 s, which suggests a significant change in CRAC channels P_o in that time [86]. This property of I_CRAC was utilized to estimate monovalent CRAC single-channel currents using an approach similar to that of Zweifach and Lewis [87]. In these experiments, the variance of Na⁺ current through I_CRAC also exhibited linear dependence on the current amplitude, supporting the notion of low P_o of CRAC channels [70]. However, the calculated unitary CRAC channel conductance of 2.6 pS in the absence of divalent cations was significantly higher than what would be expected from the estimates of CRAC unitary conductance in 110 mM Ca²⁺ [70], considering that the removal of divalent cations causes only about a 7–8-fold increase in I_CRAC amplitude. The discrepancy was later explained by a possible contamination of these recordings with endogenous MIC/TRPM7 channels that were incompletely blocked by 3 mM MgCl₂ in the pipette solution [63]. Using a higher internal concentration of Mg²⁺ (8 mM), Prakriya and Lewis reported a unitary monovalent cation (Na⁺) CRAC conductance of ∼0.2 pS, which agreed well with Ca²⁺ unitary conductance [63].

All measurements described earlier were based on the assumption that the observed changes in I_CRAC amplitude resulted from changes in P_o and not the number of functional CRAC channels on the plasma membrane. The linear dependence of variance on current amplitude was explained by low P_o of CRAC channels [70]. The linear variance-current plot, however, could result from the changes in the number of active CRAC channels during I_CRAC development and depotentiation in divalent cation-free solutions, with constant and high P_o [89]. To investigate this possibility, Prakriya and Lewis used nonstationary noise analysis of Na⁺ current through CRAC channels in the presence of a range of micromolar Ca²⁺ concentrations in the bath solution [89]. An application of up to 20 μM of Ca²⁺ to the bath solution increased the Na⁺ current noise, although the amplitude of the current declined [89], which suggested that, indeed, the P_o of CRAC channels was above 0.5 and the previous assumption of low P_o of CRAC channels was incorrect. The variance-current plot of the data obtained using a Ca²⁺ block of Na⁺ CRAC conductance followed a parabolic function (Equation 1.1), giving a CRAC Na⁺ conductance of ∼0.7 pS and P_o of about 0.8 [89]. Similar results were later obtained for overexpressed Orai1/STIM1 and Orai3/STIM1 channels [95,96]. In conclusion, a higher than previously thought single-channel conductance and high P_o of CRAC channels opens a possibility of direct single-channel current measurements. The single-channel conductance of 0.7 pS corresponds to a 70 fA unitary current per 100 mV of driving force. Assuming that the equilibrium potential for Na⁺ is about +50 mV, the amplitude of the monovalent cation unitary CRAC current at a membrane potential of -100 mV should be in the vicinity of 0.1 pA. A single-channel current of such amplitude can be recorded using low-noise patch-clamp amplifiers and appropriate filtering, provided that the right conditions for the current activation are met [97]. It remains to be determined, however, if this can be achieved in practice for CRAC channels.

1.3.7. Heterologously Expressed Orai/STIM Channels

The molecular components of CRAC channels were discovered more than a decade ago and include Orai1-3 (CRACM1-3) pore subunits and STIM1-2, ER resident luminal calcium sensors (reviewed in [33,35] and Chapters 2 and 3). Thus, mammalian cells express three different pore subunits, which was not predicted before they were cloned. Orai1 and Orai2 amino acid sequences are ∼60% homologous. Orai3 also has a high percentage of homology with the remaining members: ∼63% with Orai1 and ∼66% with Orai2. In the transmembrane domains the homology percentages are even higher, reaching 90% [98,99]. All three isoforms are expressed in human T lymphocytes [82]; however, a familial defect in Orai1 results in severe combined immunodeficiency even in the presence of normal Orai2 and Orai3 expressed in these cells. This strongly suggests that Orai2 and 3 cannot substitute for Orai1 function, at least in that case [100]. It should be noted that in cells where Orai1 expression has been knocked down with siRNA, small SOCE signals mediated by Orai2 or Orai3 are still evident [101,102].

When coexpressed with STIM1, all three Orai proteins give rise to robust inwardly rectifying currents (Figure 1.3). Orai1-3 isoforms are permeable to Ca²⁺ and some other divalent cations (Ba²⁺, Sr²⁺) [90,103]. For Orai2 and Orai3, inward Ba²⁺ currents were larger than for Orai1, although they could only be detected in the presence of Na⁺ but not TEA, suggesting that Na⁺ may carry part of the current [103]. In the complete absence of divalent cations, Orai1-3 readily conduct monovalents, such as Na⁺, Li⁺, and Rb⁺ [103,104]. Interestingly, Orai isoforms can be distinguished in heterologous expression systems by their sensitivity to 2-aminoethyl diphenyl borinate (2-APB), a compound originally identified as an IP₃ receptor blocker [105] (see Chapter 16). Orai1 and 2 are potentiated by low (5–10 μM) but inhibited by high 2-APB (above 50 μM) concentrations [106]. By contrast, 2-APB activates Orai3/STIM1, altering its I-V relation, which is normally inwardly rectifying (Figures 1.3 and 1.4). 2-APB-mediated activation results in an outwardly rectifying current, which can be conducted by both Cs⁺ and Na⁺. Similar to native CRAC channels, overexpressed Orai1 and Orai2 conduct Cs⁺ poorly (∼10% of Na⁺ conductance) in the absence of divalent cations. Consequently, it has been suggested that 2-APB widens the Orai3 pore and allows it to conduct monovalent cations even in the presence of Ca²⁺ [107]. In contrast to Orai3, 2-APB does not change Orai1 and Orai2 selectivity [106]. Whether this divergence of 2-APB effects for overexpressed Orai1-3 can be used to distinguish endogenous Orai isoform activity is still unclear. It remains to be discovered if the Orai3 nonselective channel state can be achieved under physiological conditions without 2-APB and what that means in terms of cellular calcium metabolism.

Figure 1.3

Instantaneous I-V plots of Orai1-3/STIM1-mediated I_CRAC. Traces were recorded in response to 100 ms voltage ramps ranging from -120 to 120 mV in HEK293T cells transfected with STIM1 and Orai1, Orai2, or Orai3 cDNA as previously described [90]. External (more...)

Figure 1.4

2-APB modified Orai3 conducts both Na⁺ and Ca²⁺. Whole-cell patch-clamp recordings of HEK293 cells transfected with Orai3 and STIM1. (a, c) Time courses of inward (black) and outward (red) current development in the presence of 50 μM 2-APB. (b, (more...)

Orai1 to STIM1 transfection ratios significantly influence the electrophysiological properties of these channels. Specifically, the kinetics of the channel activation and inactivation were changed in addition to selectivity to divalent metals (Ba²⁺ and Ca²⁺). Increasing STIM1 to Orai1 expression ratios results in an inactivating current whereas Orai1 excess to STIM1 leads to non-inactivating currents [90]. Orai currents can be evoked by coexpressing full length STIM1 but also by overexpressing only the SOAR region [37] (discussed in Chapter 2).

Orai/STIM channels have primarily been studied in human embryonic kidney (HEK) cells transfected with their various isoforms. The recording conditions are essentially the same as for recording the native CRAC channels. The internal solution should contain calcium chelators alone or with IP₃ for depleting ER Ca²⁺ stores [104,106]. However, in most cases, overexpressed Orai/STIM channels are to some extent constitutively active, unlike CRAC channels in Jurkat or RBL cells [37]. The overexpression of either Orai or STIM proteins in isolation does not usually result in large CRAC currents.

The murine and human Orai2 exist in two forms, long and short [108–110]. The Orai2 expression pattern is somewhat different from that of Orai1, although in many cases they are coexpressed [109]. For example, neurons and chondrocytes show high expression of Orai2, even though its function in these cells is unknown [111]. When coexpressed with STIM1, human Orai2 form inwardly rectifying channels (Figure 1.3) sharing many biophysical properties with Orai1 [103]. In an early detailed study of overexpressed murine Orai2, Gross and colleagues recorded currents from HEK cells overexpressing both long and short splice variants [108]. Orai2 and STIM1 were transfected at a 2:1 ratio. Infusion of cells with high EGTA and IP₃-containing buffers evoked currents reminiscent of native CRAC channels. Interestingly, the levels of expression depended on the cell type chosen for transfection, HEK vs. RBL. One striking difference of Orai2 from Orai1 was the apparently increased (slow) calcium-dependent inactivation. It was concluded that calcium influx through Orai2 channels causes the inactivation that can be relieved by the fast removal of calcium from the vicinity of the channels. Inactivation was proportional to the peak current amplitude. The dependence of channel expression on the type of the background cell line was explained by the fact that HEK cells express very little Orai1 and Orai2 protein detected in Western blots, whereas RBL cells express both channels at high levels. Accordingly, the overexpression of STIM1 alone in HEK cells did not increase CRAC current density but doubled it in RBL cells. When coexpressed with Orai1, Orai2 was shown to reduce current expression, suggesting that it can form heteromers with other Orai isoforms [108]. Similar conclusions were reached by Inayama and colleagues by coexpressing Orai1 E106Q point mutant with the wild-type Orai2 in chondrocyte cell lines [111].

1.4. TRPV5 and TRPV6 Channels

Acknowledgment

We thank Pavani Beesetty, Wright State University, for performing the single-cell calcium imaging experiments depicted in Figure 1.1.

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J. Ashot Kozak

Department of Neuroscience, Cell Biology and Physiology

Boonshoft School of Medicine

Wright State University

Dayton, Ohio

Grigori Rychkov

School of Medicine

University of Adelaide

and

South Australian Health and Medical Research Institute

Adelaide, South Australia, Australia