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Biological Research
Print version ISSN 0716-9760
Biol. Res. vol.37 no.4 Santiago 2004
http://dx.doi.org/10.4067/S0716-97602004000400024
Biol Res 37: 665-674, 2004 ARTICLE Interplay between ER Ca2+ uptake and release fluxes in neurons and its impact on [Ca2+] dynamics
DAVID FRIEL
Dept. of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA Dirección para Correspondencia ABSTRACT
In neurons, depolarizing stimuli open voltage-gated Ca2+ channels, leading to Ca2+ entry and a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i). While such [Ca2+]i elevations are initiated by Ca2+ entry, they are also influenced by Ca2+ transporting organelles such as mitochondria and the endoplasmic reticulum (ER). This review summarizes contributions from the ER to depolarization-evoked [Ca2+]i responses in sympathetic neurons. As in other neurons, ER Ca2+ uptake depends on SERCAs, while passive Ca2+ release depends on ryanodine receptors (RyRs). RyRs are Ca2+ permeable channels that open in response to increases in [Ca2+]i, thereby permitting [Ca2+]i elevations to trigger Ca2+ release through Ca2+-induced Ca2+ release (CICR). However, whether this leads to net Ca2+ release from the ER critically depends upon the relative rates of Ca2+ uptake and release. We found that when RyRs are sensitized with caffeine, small evoked [Ca2+]i elevations do trigger net Ca2+ release, but in the absence of caffeine, net Ca2+ uptake occurs, indicating that Ca2+ uptake is stronger than Ca2+ release under these conditions. Nevertheless, by increasing ER Ca2+ permeability, RyRs reduce the strength of Ca2+ buffering by the ER in a [Ca2+]I-dependent manner, providing a novel mechanism for [Ca2+]i response acceleration. Analysis of the underlying Ca2+ fluxes provides an explanation of this and two other modes of CICR that are revealed as [Ca2+]i elevations become progressively larger.
Key words: Calcium dynamics, sympathetic neurons, endoplasmic reticulum, ryanodine receptors.
Abbreviations: Ca2+: ionized free Ca; [Ca2+]: Ca2+ concentration; [Ca2+]i, cytoplasmic [Ca2+]; [Ca2+]ER, ER [Ca2+]. ER: Endoplasmic reticulum; EPMA: Electron probe microanalysis; RyR: ryanodine receptors; SERCA: sarco-endoplasmic reticulum Ca ATPase; Tg: thapsigargin; t-BuBHQ, 2,5-Di-(t-butyl)-1,4-hydroquinone. INTRODUCTION
Many physiological stimuli produce their intracellular effects by increasing the intracellular free calcium concentration ([Ca2+]) (Carafoli, 2004, this issue). Such [Ca2+] elevations can be elicited by release of Ca2+ from intracellular stores or by promoting Ca2+ entry from the extracellular medium. Ca2+-induced Ca2+ release (CICR) is an intriguing mechanism found in many excitable cells that employs both pathways. Here, Ca2+ entry through surface membrane Ca2+ channels triggers Ca2+ release from internal stores, principally the endoplasmic reticulum (ER). This review describes the effects of CICR on [Ca2+] responses induced by depolarizing stimuli in sympathetic neurons. While some of these effects are very similar to those previously described in other excitable cells, other effects are in fact quite surprising. However, after considering the underlying Ca2+ transport mechanisms that define the rate of net Ca2+ transport between the ER and cytoplasm, it becomes clear that these effects are simple consequences of the interplay between ER Ca2+ uptake and release pathways that are differentially regulated by Ca2+. This review is not intended to be a comprehensive discussion of the role of the endoplasmic reticulum in calcium signaling, but rather a brief summary of our work on sympathetic neurons over the last few years (for a more extensive review of calcium signaling in these cells, see Friel, 2003). Space limitations make it impossible to cite all the original studies that we have drawn upon, but references to several review articles have been included to help guide interested readers to the work of other investigators on a variety of preparations.
GENERAL BACKGROUND
Previous studies in a variety of cells have shown that [Ca2+]i responses evoked by depolarizing stimuli are influenced by multiple factors, including Ca2+ entry and extrusion across the plasma membrane, Ca2+ uptake and release from internal stores, and Ca2+ binding to endogenous and exogenous buffers. One of the properties of calcium signaling that makes it so interesting and complex is that the impact of a given Ca2+ transport or buffering system on stimulus-evoked calcium signals depends not only on its properties in isolation, but on the other Ca2+ handling systems with which it functionally interacts in vivo. Early work from my laboratory described how cytoplasmic and mitochondrial calcium dynamics depend on the interplay between Ca2+ transport across the plasma membrane and calcium uptake and release by mitochondria (Colegrove et al., 2000a,b; for a review see Friel, 2003). These studies showed how multiple Ca2+ transport systems that are regulated by Ca2+ in quantitatively different ways collectively give rise to evoked calcium signals with complex temporal profiles that are expected to have a strong impact on downstream processes that `read out' the Ca2+ signal. An important step in this work was the development of experimental approaches for dissecting the net Ca2+ fluxes that drive changes in calcium concentrations within particular cellular compartments into components representing individual transport pathways. This made it possible to determine how the rate of transport by each system varies with calcium concentration and use computer simulations to test if these transport systems account for evoked [Ca2+] signals that are observed experimentally. This review will summarize a complementary study that was designed to elucidate how Ca2+ transport by the ER participates in neuronal calcium signaling. The goal of the study was to determine how CICR arises from the functional interplay between ER Ca2+ uptake and release pathways, and those regulating Ca2+ extrusion across the plasma membrane. The main conclusions can be summarized as follows. During depolarization-induced Ca2+ entry: (1) The ER can act as either a Ca2+ source or sink, depending on the size of the evoked [Ca2+]i elevation, with net uptake favored at low [Ca2+]i, and net release favored at high [Ca2+]i; (2) The transition from sink to source that occurs as [Ca2+]i increases can be explained by Ca2+ uptake and release pathways whose activities are regulated by Ca2+ in quantitatively different ways.
BASIC PROPERTIES OF ER Ca2+ HANDLING
The ER is an important component of Ca2+ signaling in most, if not all, non-muscle cells (Meldolesi and Pozzan, 1998). Ca2+ transport by the ER is thought to have at least three main functions. First, it permits the ER to act as a Ca2+ pool that can be mobilized by various IP3-generating stimuli (e.g. Foskett and Mak, 2004). Second, ER Ca2+ transport modulates evoked changes in [Ca2+]i, thereby influencing all cellular processes that are regulated by cytoplasmic Ca2+. Finally, intraluminal Ca2+ participates in protein processing (Verkhratsky and Petersen, 2002). Net Ca2+ transport by the ER is accomplished by a set of distinctive Ca2+ transport systems (here broadly interpreted to include channels, pumps and exchangers). Ca2+ uptake is regulated by Ca2+ pumps termed SERCAs (sarco- and endoplasmic reticulum Ca ATPases) and passive Ca2+ release is regulated by channels that open in response to elevations in [Ca2+]i and permit Ca2+ to flow passively down a steep concentration gradient into the cytoplasm (See Carafoli, 2004, this issue). Ca2+ release channels are particularly interesting because they render the Ca2+ permeability of the ER sensitive to [Ca2+]i, setting the stage for CICR (Bezprozvanny et al., 1991; for reviews, see Kuba, 1994; Verkhratsky and Shmigol, 1996; and Usachev and Thayer, 1999). Two major classes of Ca2+ release channels have been identified: ryanodine receptors (RyRs) and inositol (1,4,5)-trisphosphate receptors, which can be distinguished based on Ca2+-sensitivity, pharmacology, and expression patterns that define their distinctive contributions to Ca2+ signaling in different cells (e.g. see Danila and Hamilton, 2004; Foskett and Mak, 2004, both in this issue).
How does the ER contribute to depolarization-evoked calcium responses in neurons?
Previous studies have described the ER as either a Ca2+ source or sink during depolarization-induced [Ca2+]i elevations, in some cases, even within the same cell type. While these modes of signaling are expected to have very different functional effects on intraluminal and cytoplasmic Ca2+ binding proteins, until recently the stimulus parameters that determine whether net Ca2+ uptake or release occurs have been unclear. We therefore conducted a study to determine the specific conditions of stimulation that promote net Ca2+ uptake vs. net Ca2+ release. We then sought to understand what distinguishes these conditions based on the properties of the underlying Ca2+ transport systems. Sympathetic neurons in primary culture were used as model cells, and cytoplasmic Ca2+ levels were monitored using the fluorescent Ca2+ indicator Fura-2. Ca2+ entry was stimulated by depolarizing cells from near the resting potential (~-70 mV) to various voltages ranging from _35 to _20 mV under voltage clamp (perforated patch conditions), or by exposing cells to external solutions containing high K+, using equimolar replacement of extracellular Na+; the concentrations of K+ that were used, 30 and 50 mM, were shown by direct recording of membrane potential to produce steady depolarizations to approximately -35 and -20 mV respectively. These two methods of stimulation produce very similar [Ca2+] responses, with the primary difference being the much more abrupt depolarization that is possible under voltage clamp compared to high K+ depolarization, which is rate-limited by changes in the external solution bathing individual cells (~0.2 s). Additional studies carried out in collaboration with Brian Andrews and colleagues at the NIH provided measurements of the total Ca concentration within the ER ([Ca]ER) and how it changes in response to depolarizing stimuli using electron probe microanalysis (EPMA).Membrane depolarization opens voltage-gated Ca2+ channels, initiating a rise in [Ca2+]i. Evidence that Ca2+ transport by the ER might contribute to these responses comes first from the observation that under resting conditions, rapid application of SERCA inhibitors, such as thapsigargin (Tg, 0.2-1.0 mM) or t-BuBHQ (50-100 mM), elicit a transient rise in [Ca2+]i. That these [Ca2+]i transients are observed in the absence of extracellular Ca2+ and occur without delay after applying the inhibitor provides evidence for ongoing Ca2+ transport at rest during which active Ca2+ uptake is balanced by passive Ca2+ release, such that sudden inhibition of uptake unmasks release, leading to a rise in [Ca2+]i. Since cytoplasmic Ca2+ serves as a substrate and/or modulator of both the uptake and release pathways, changes in [Ca2+]i initiated by Ca2+ entry are expected to have effects on both transport pathways. Moreover, since the rate of net ER Ca2+ transport that determines how intraluminal Ca concentration changes during stimulation depends on the relative rates of uptake and release, differences in the Ca2+ sensitivity of these transport activities can impart complex temporal properties to evoked calcium responses. Initial evidence suggesting that ryanodine-sensitive Ca2+ release channels, in particular, contribute to depolarization-evoked responses came from the finding that [Ca2+]i responses are amplified if cells are depolarized in the presence of caffeine (Fig. 1). Caffeine has previously been shown to increase the Ca2+-sensitivity of RyRs, causing them to open with high probability even at low resting [Ca2+]i levels (Zucchi and Ronca-Testoni, 1997). Under control conditions, Ca2+ entry induced by weak depolarization from -70 to -35 mV under voltage clamp elicits a slow increase in [Ca2+]i from a resting level of 50-100 nM to ~300 nM. In contrast, in the presence of caffeine, Ca2+ entry triggers a rapid [Ca2+]i spike suggestive of net CICR, followed by a return to the same elevated steady level seen in control responses. The effects of caffeine on these evoked [Ca2+]i responses cannot be explained by changes in voltage-sensitive Ca2+ entry and are blocked by Tg and ryanodine (1 mM), indicating that response amplification depends on the activity of a ryanodine-sensitive Ca2+ release pathway, presumably representing RyRs (Friel and Tsien, 1992, Albrecht et al., 2001).
SMALL [Ca2+]I ELEVATIONS ELICITED BY WEAK DEPOLARIZATION STIMULATE ER CALCIUM ACCUMULATION
While these and other observations indicate that sympathetic neurons possess a ryanodine-sensitive Ca2+ release pathway, which allows the Ca2+ entry to trigger net CICR when modified by caffeine, they do not address the role of this pathway in regulating ER and cytoplasmic Ca2+ dynamics in the absence of caffeine. We found that under control conditions, weak depolarizations that raise [Ca2+]i to ~300 nM stimulate net Ca2+ accumulation by the ER. This was suggested by the observation that [Ca2+]i elevations are accelerated after cells have been treated with Tg, as if Tg disables a Ca2+ buffering system that normally sequesters Ca2+ as it enters the cytoplasm during depolarization; no effect on voltage-gated Ca2+ entry was detectable at the Tg concentrations employed (Fig. 2). Direct confirmation of net calcium uptake was obtained by measuring evoked changes in total ER Ca concentration, using EPMA (Hongpaisan et al., 2001) (see Fig. 4). Therefore, in sympathetic neurons, small [Ca2+]i elevations (~300 nM) promote net calcium uptake, rather than net Ca2+ release.
EFFECTS OF RYR ACTIVITY ON THE RATE OF Ca2+ ACCUMULATION DURING WEAK DEPOLARIZATION
How can net Ca2+ uptake by the ER during weak stimulation be reconciled with the presence of a ryanodine-sensitive CICR pathway that might be expected to favor triggered Ca2+ release from the ER? A key piece of information was provided by the following observation: after exposing cells to ryanodine (1 mM), depolarization-evoked [Ca2+]i elevations show a significantly slower onset and recovery than control responses (Fig. 3). As with the effect of Tg, this effect could not be explained by ryanodine-induced changes in voltage-sensitive Ca2+ entry. Since the direction of net Ca2+ transport by the ER depends on the relative rates of Ca2+ uptake and release via distinct pathways, the finding that small [Ca2+]i elevations stimulate net calcium uptake means that under these conditions, the average rate of Ca2+ uptake exceeds the average rate of Ca2+ release. This raises the following question: how would Ca2+-dependent activation of RyRs contribute to net Ca2+ transport by the ER when it acts as a Ca2+ buffer? During stimulation, RyR activation would be expected to increase the Ca2+ permeability of the ER. For a given electrochemical driving force that favors passive Ca2+ release, this would increase the rate of passive release. If uptake is faster than release, the overall consequence of a small increase in release rate would be a reduced imbalance between uptake and release rates, leading to slower net Ca2+ uptake. During weak stimulation, RyR activation would therefore accelerate evoked [Ca2+]i elevations not by promoting net Ca2+ release from the ER, but by reducing the rate of net uptake. This provides a potential explanation of the observed effects of ryanodine. If ryanodine prevents a Ca2+-induced increase in RyR activity during stimulation, it would lower the rate of passive Ca2+ release, increase the imbalance between uptake and release rates, and thereby enhance net Ca2+ uptake. Thus, in the presence of ryanodine, small depolarizations that normally stimulate weak Ca2+ accumulation would cause more powerful accumulation, simply because the uptake pathway now operates in parallel with a smaller leak. Overall, ryanodine would cause the ER to become a more powerful Ca2+ buffer during periods of stimulated Ca2+ entry. We carried out two series of experiments to test this idea. First, if the interpretation presented above is correct, then Tg should reverse the effects of ryanodine. We found that this is indeed the case (Albrecht et al., 2001). Second, direct measurement showed that following treatment with ryanodine, elevations in intraluminal total Ca concentration induced by weak depolarization are larger than controls, confirming the idea that ryanodine increases the average rate of net Ca2+ uptake during stimulation. Interestingly, ryanodine also reduced the basal ER total calcium concentration by ~60%, which can be explained, at least in part, by a parallel increase in basal ER Ca2+ permeability. This increase was presumably the result of an increase in steady-state RyR open probability like that observed when purified RyRs in planar lipid bilayers are exposed to ryanodine at concentrations that are below those causing the channel blockade (Sutko et al. 1997).
LARGE [Ca2+]i ELEVATIONS STIMULATE NET Ca2+ RELEASE
We found that with stronger depolarizations that raise [Ca2+]i to higher levels, the ER undergoes a transition from net Ca2+ uptake to net Ca2+ release. While weak depolarizing stimuli (Vm~-35 mV) that raise [Ca2+]i from a resting level of 50-100 nM to ~300 nM lead to net Ca2+ uptake, stronger depolarizations (Vm~-20 mV) that produced intermediate [Ca2+]i elevations (400-600 nM) lead to little or no net ER Ca2+ transport. In contrast, stimuli that raise [Ca2+]i to levels in excess of ~1 mM cause net Ca2+ release (Fig. 4) (see Hongpaisan et al., 2001).
ANALYSIS OF THE UNDERLYING Ca2+ FLUXES
We investigated the basis for the observed biphasic [Ca+2]i-dependence of net ER Ca2+ transport. Since the intraluminal calcium concentration changes under the influence of a net Ca2+ flux whose direction depends on the relative rates of Ca2+ uptake and release via different pathways, we predicted that the biphasic [Ca2+]i-dependence of evoked changes in [Ca]ER results from different [Ca2+]i-sensitivities of the Ca2+ uptake and release rates. To test this idea, we examined the [Ca2+]i-dependence of the rates of Ca2+ uptake via SERCAs (JSERCA) and of passive Ca2+ release by the ER (JRelease), which depends on both the driving force for Ca2+ release ([Ca2+]i-[Ca2+] ER) and the Ca2+ permeability of the ER (PER) (Albrecht et al., 2002). Figure 5B shows smooth curves based on measurements of the fluxes that together define the net ER Ca2+ flux (JER= JSERCA + JRelease). The quantitative properties of these fluxes provide an explanation for the biphasic [Ca2+]i-dependence of evoked changes in [Ca]ER. At low [Ca2+]i, JSERCA changes more steeply with [Ca2+]i than does JRelease, leading to net Ca2+ uptake as [Ca2+]i rises, while at high [Ca2+]i the reverse is true, accounting for net Ca2+ release. The increase in the magnitude of JRelease reflects the [Ca2+]i-dependence of PER, which because it is highly sensitive to caffeine and ryanodine, appears to represent the contribution to ER Ca2+ permeability from ryanodine sensitive Ca2+ release channels (Albrecht et al, 2002). Figure 5C shows the fluxes that together define the net cytoplasmic Ca2+ flux (Ji), which determines how [Ca2+]i changes with time. The interplay between JER, which increases biphasically with [Ca2+]i, and the rate of Ca2+ extrusion across the surface membrane (JExtru), which in turn increases monotonically with [Ca2+]i, leads to the separation of the [Ca2+]i range into three domains displaying distinct modes of CICR. When [Ca2+]i is above the resting level but low enough so that RyR activity is weak, Ji and JER are both outward (positive) fluxes (Mode 1 CICR). JER is positive because passive Ca2+ release is slower than Ca2+ uptake, causing the ER to act as a buffer. In this mode, activation of the [Ca2+]i-sensitive permeability during stimulation reduces the rate of Ca2+ accumulation and accelerates the rise in [Ca2+]i as compared to the case where PER is constant at its resting level. Over the intermediate [Ca2+]i range, Ji is positive but JER is negative (Mode 2 CICR) because passive Ca2+ release is faster than uptake. In this [Ca2+]i domain, net Ca2+ release amplifies the effects of stimulated Ca2+ entry on [Ca2+]i, causing [Ca2+]ER to decline to an extent that is graded with [Ca2+]i. Finally, at higher [Ca2+]i levels, both Ji and JER are inward fluxes (Mode 3 CICR). A brief stimulus that brings [Ca2+]i within this range would stimulate Ca2+ release at such a high rate that it would overwhelm Ca2+ extrusion, leading to a regenerative rise in [Ca2+]i and fall in [Ca2+]ER. The zero crossing in this case represents the threshold for regenerative net CICR. It should be noted that while this discussion has focused on CICR under the control of RyRs, the general ideas apply equally well to other types of Ca2+ release channels, e.g. InsP3Rs.
Our results underscore a basic ambiguity in the phrase "Ca2+-induced Ca2+ release," which arises because there is a distinction between passive Ca2+ transport via a CICR pathway and net Ca2+ transport by the ER. CICR is usually used to refer to net Ca2+ release, but our results indicate that activation of a Ca2+-sensitive release pathway can have the alternate effect of attenuating net ER Ca2+ accumulation. The term CICR could in principle refer to either passive release via a Ca2+-sensitive permeability without reference to the direction of net organellar Ca2+ movement, or to Ca2+-induced net Ca2+ release. Since the second definition necessarily involves the relationship between a CICR pathway and other transport systems, we prefer the first definition and use `net CICR' to describe the case in which CICR leads to a reduction in intraluminal Ca2+ levels. According to this usage, CICR refers to a Ca2+-induced increase in a passive Ca2+ release whose impact on intraluminal Ca2+ levels is context-dependent.
SUMMARY AND CONCLUSIONS
Ca2+ is an important signaling intermediate in virtually all cells that produces its effects by interacting with Ca2+ sensors in a manner that depends critically on Ca2+ concentration. Therefore, there is a strong rationale for understanding the physiological determinants of [Ca2+] dynamics. The free Ca2+ concentration is tightly controlled in all cellular compartments by specific Ca2+ transport and buffering systems that have been investigated in isolation, but largely because of technical difficulties in measuring rates of transport in situ have received little attention in intact cells. This review provides an overview of work that we have done to elucidate the functional properties of ER Ca2+ transport systems expressed in sympathetic neurons and how they operate together to orchestrate stimulus-evoked Ca2+ signals. Our results show how multiple Ca2+ transporters operating in parallel can impart to Ca2+ dynamics a complicated dependence on Ca2+ concentration, illustrating the importance of obtaining quantitative functional descriptions of Ca2+ transport systems in intact cells. Our results also demonstrate that in addition to exhibiting different spatial signaling domains, cells also show distinctive Ca2+ concentration `domains' in which there are unique patterns in the way [Ca2+] changes in different cellular compartments, patterns that are likely to have unique effects on cell function.
ACKNOWLEDGEMENTS
The author would like to thank Meredith Albrecht, S. Brian Andrews, Stephen Colegrove, Jarin Hongpaisan and Natalia Pivovarova for their contributions to this work.
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Received: January 21, 2004. Accepted: March 22, 2004. |