Inositol trisphosphate and calcium signaling

Inositol trisphosphate and calcium signaling
Inositol trisphosphate is a second messenger that controls many cellular processes by generating internal calcium signals. It operates through receptors whose molecular and physiological properties closely resemble the calcium-mobilizing ryanodine receptors of muscle. This family of intracellular calcium channels displays the regenerative process of calcium-induced calcium release responsible for the complex spatiotemporal patterns of calcium waves and oscillations. Such a dynamic signalling pathway controls many cellular processes, including fertilization, cell growth, transformation, secretion, smooth muscle contraction, sensory perception and neuronal signalling.
The endoplasmic reticulum and neuronal calcium signaling
The endoplasmic reticulum (ER) is a multifunctional signalling organelle regulating a wide range of neuronal functional responses. The ER is intimately involved in intracellular Ca2+ signalling, producing local or global cytosolic calcium fluctuations via Ca2+-induced Ca2+ release (CICR) or inositol-1,4,5-trisphosphate-induced Ca2+ release (IICR). The CICR and IICR are controlled by two subsets of Ca2+ release channels residing in the ER membrane, the Ca2+-gated Ca2+ release channels, generally known as ryanodine receptors (RyRs) and InsP3-gated Ca2+ release channels, referred to as InsP3-receptors (InsP3Rs). Both types of Ca2+ release channels are expressed abundantly in nerve cells and their activation triggers cytoplasmic Ca2+ signals important for synaptic transmission and plasticity. The RyRs and InsP3Rs show heterogeneous localisation in distinct cellular sub-compartments, conferring thus specificity in local Ca2+ signals. At the same time, the ER Ca2+ store emerges as a single interconnected pool fenced by the endomembrane. The continuity of the ER Ca2+ store could play an important role in various aspects of neuronal signalling. For example, Ca2+ ions may diffuse within the ER lumen with comparative ease, endowing this organelle with the capacity for “Ca2+ tunnelling”. Thus, continuous intra-ER Ca2+ highways may be very important for the rapid replenishment of parts of the pool subjected to excessive stimulation (e.g. in small compartments within dendritic spines), the facilitated removal of localised Ca2+ loads, and finally in conveying Ca2+ signals from the site of entry towards the cell interior and nucleus.
The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons
The smooth endoplasmic reticulum (SER) is a well-characterized buffer and source of Ca2+ in both axonal and dendritic compartments of neurons. Ca2+ release from the SER can be evoked by stimulation of the ryanodine receptor or the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptor. Both receptors can couple to the activation of neurotransmitter-gated receptors and voltage-gated Ca2+ channels on the plasma membrane, thus enabling the SER to discriminate between different types of neuronal activity. In axonal terminals, Ca2+-induced Ca2+ release (CICR) mediates spontaneous, evoked and facilitated neurotransmission. Store release might also regulate the mobilization and recycling of synaptic vesicles. In the dendritic compartment, the distribution of Ins(1,4,5)P3 receptors and ryanodine receptors influences the intracellular encoding of neuronal activity. Thus, the functionality of the Ca2+ store can affect both the polarity and the spatial extent of Ca2+-dependent shifts in synaptic efficacy. In hippocampal neurons, for example, CICR in the spine heads underlies homosynaptic plasticity, whereas heterosynaptic plasticity is mediated by Ins(1,4,5)P3-dependent Ca2+ signalling. Purkinje neurons primarily express Ins(1,4,5)P3 receptors in the spine heads, and long-term depression of synaptic efficacy is crucially dependent on Ins(1,4,5)P3.
Calcium: outside/inside homeostasis and signaling
More and more data accumulate concerning calcium dependent effects in all compartments of cells. The higher the organism in evolution the more calcium becomes involved. Inspection of the data while looking for an explanation of the involvement of calcium in metabolism, nuclear functions, control over pumps, external activities, mineralisation and so on leads one to suppose that calcium has an integrating function. The implication is that calcium flow is a large network connecting the environment, the cytoplasm, vesicles, organelles, the nucleus and in higher species, organs. There is the possibility then that calcium ion functions are being analysed, often in vitro, in a bit by bit reductionist manner while in vivo calcium is the equivalent of an electron in complicated electrical circuits. We then should look for its connections to energy, to effects where conformational switching by calcium pulses is equivalent to magnetic triggering by electron flow and where storage in vesicles is equivalent to condenser-like devices and so on. The appearance of pulsing, of time delays in parts of circuits, and other properties of electronic circuits seen in calcium triggering are then explicable as part of calcium circuit design. No other ion can operate in the same way due to the peculiarities of the calcium ion, its size, charge, ionisation potential and its availability which allow it both to flow rapidly yet to bind considerably.
The calcium (Ca2+) ion, as a ubiquitous intracellular messenger, regulates many different cellular functions, including contraction, secretion, metabolism, gene expression, cell survival and cell death[1]. Likewise, reactive oxygen species (ROS) such as superoxide anion (O2·_ ) and hydrogen peroxide (H2O2) are widely involved in physiological and pathophysiological processes through oxidizing proteins, lipids and polynucleotides[2,3]. Recent studies have underscored the notion that the Ca2+ and ROS signaling systems are intimately integrated such that Ca2+-dependent regulation of components of ROS homeostasis might influence intracellular redox balance, and vice versa. On one hand, a number of ROS-generating and antioxidant systems of living cells have been shown to be Ca2+-dependent[4,5]. Con-versely, regulation of Ca2+ signals can be redox-dependent. The incredible versatile Ca2+ signals, depending on an extensive Ca2+ signaling toolkit, can act in various contexts of space, time and amplitude[1,6]. Redox modulation of components of the Ca2+ signaling toolkit occurs in different physiological and pathological processes, resulting in altered amplitude and spatiotemporal characteristics of Ca2+ signals. In this brief review, we discuss the specific mechanisms underlying the interaction and integration of these two powerful intracellular signaling systems in different types of cells.
Ca2+ modulation of ROS homeostasis
ROS play an important role in physiological cellular functions by activating several enzymatic cascades and transcription factors[7]. Excessive ROS signals, however, are detrimental, causing Ca2+ overload, mitochondrial depolariza-tion, cytochrome c release, lipid peroxidation, transcription factor activation and DNA damage, and lead to apoptotic and non-apoptotic cell death. As such, oxidative stress is increasingly recognized as a causative factor in the development of a diverse array of diseases, including neurodegenerative diseases, malignant diseases, diabetes mellitus, atherosclerosis, and ischemia/reperfusion injury[7]. The intracellular redox state reflects the dynamic balance between ROS production and the antioxidant capacity of the cell. Increasing evidence indicates that intracellular Ca2+ modulates both ROS generation and ROS clearance processes and thereby shifts the redox state toward either a more oxidized or reduced direction in a context-sensitive manner.
Ca2+-induced ROS production There are many intracellular ROS generation sites (Figure 1). Of them, the electron transport chain resides on the mitochondria and there are plenty of extramitochondrial enzymes in the plasma membrane or in the cytosol, such as cell-surface NADPH-oxidase, peroxisomes, cytochrome P450, xanthine oxidase, cyclooxy-genase, and lipooxygenase[8,9]. Mitochondria provide the main source of physiological ROS production, with 1%_2% of total electrons flowing through the respiratory chain leaking to produce ROS[10]. The primal ROS made by electron transport chains is O2·_ , which is changed to H2O2 either by spontaneous dismutation or catalyzed by superoxide dismutase (SOD). One important function of mitochondrial Ca2+ is to stimulate the tricarboxylic acid (TCA) cycle[11] and oxidative phosphorylation[12_15]. Specifically, 3 dehydrogenases of the TCA cycle (pyruvate dehydrogenase, isocitrate dehydrogenase and oxoglutarate dehydrogenase)[11], the ATP synthase (complex V)[14], and the adenine nucleotide trans-locase[12] are all activated by Ca2+. Hence, Ca2+ might increase ROS generation by enhancing metabolism. During this process, more electrons leak from the respiratory chain while more O2 is consumed to produce ATP. To this end, previous studies have shown a positive correlation between mitochondrial ROS generation and the basal metabolic rate[16,17]. Interestingly, Ca2+ can also enhance ROS production when complexes of the electron transport chain are inhibited. As shown by in vitro experiments, Ca2+ stimulates ROS production in isolated rat heart mitochondria in the presence of antimycin A (complex III inhibitor)[18]. Similar observations have been made with rotenone (complex I inhibitor) treatment of brain mitochondria[19]. This phenomenon appears to be tissue-specific, because addition of Ca2+ to brain mitochondria in the presence of antimycin A does not stimulate ROS generation[19].
The underlying mechanism for Ca2+-induced mitochondrial ROS generation is not fully understood. Cadenas and Boveris proposed that mitochondria depolarization is responsible for the Ca2+ effects[18], whereas others have attributed the Ca2+ effects to the alteration of mitochondrial membrane structure[19]. Studies on isolated mitochondria[4,20_22] have demonstrated that high concentration of mitochondrial Ca2+ ([Ca2+]m) triggers mitochondrial permeability transition pore (mPTP) opening and enhances ROS production, but the cascade of events linking mPTP opening to ROS generation remains elusive. The Ca2+-induced mPTP opening can be inhibited by antioxidants such as MCI-186[23] or catalase[24]. Furthermore, nearly 100 different proteins are lost from the mitochondrial inner membrane, including cytochrome c, glutathione (GSH) and other matrix solutes during mPTP opening. In principle, any of these molecules could enhance ROS generation.
In addition to the regulation of mitochondrial ROS production, Ca2+ regulates multiple extramitochondrial ROS-generating enzymes both in physiological and pathological processes. Cell-surface NADPH oxidases, with rapid kinetics of activation and inactivation, are the most important multienzyme complexes in the generation of ROS involved in receptor-mediated signaling cascades[8]. The best studied among them is the phagocyte NADPH-oxidase, which consists of a dimer of transmembrane subunits, gp91phox and p22phox, and three cytosolic subunits, p67phox, p47phox, and rac2. An additional component, p40phox, is also associated with oxidase, but its functional role is unclear[25]. Activity of neutrophil oxidases, including NADPH-oxidase, is Ca2+-dependent[26]. Buffering intracellular or extracellular Ca2+ decreases generation of oxygen metabolites in human neutrophils[27]. NAD(P)H oxidase and its homologs are present in a variety of nonphagocytic cells including smooth muscle cells, chondrocytes, kidney epithelial cells, endothelial cells, prostate cancer cells[21], and spermatocytes[28]. In response to elevations of the cytosolic Ca2+ concentration ([Ca2+]c), NADPH oxidase 5 (NOX5), a homolog of the gp91phox subunit of the phagocyte NADPH oxidase, generates large amounts of superoxide[28], which attributes to conformation change of NOX5 induced by Ca2+[29]. It has been shown[30,31] that activities of other ROS-generating enzymes are regulated by [Ca2+]c directly or indirectly.
Ca2+ regulation of antioxidant defense system To counteract the damaging potential of ROS, cells use the antioxidant defense system, which involves both enzymatic and nonenzymatic oxidant defense mechanisms. Ca2+ can directly activate antioxidant enzymes, such as plant catalase and GSH reductase, increase the level of SOD in animal cells[5], and induce mitochondrial GSH release early in Ca2+-induced mPTP opening[4]. Alternatively, calmodulin (CaM), a ubiquitous Ca2+-binding protein, interacts with antioxidant enzymes involved in ROS homeostasis. CaM binds to and activates some plant catalases in the presence of Ca2+, and downregulates H2O2 levels[32]. Collectively, these studies indicate that Ca2+ plays dual roles in regulating ROS homeostasis. The net Ca2+ effects on ROS generation and annihilation appear to be tissue-specific and context-sensitive, and, within a given cell, are differentially regulated in local subcellular compartments.
ROS regulation of Ca2+ signaling
The Ca2+ signaling system comprises hundreds and up to thousands of protein players that are involved in virtually every aspect of cell biology and physiology. Any influence on the Ca2+ signaling toolkit might change the spatiotemporal profile of local and global Ca2+ signals, contributing to the efficiency, specificity and complexity of Ca2+ signal transduction. In this section we briefly discuss how ROS modify key Ca2+ signaling proteins and reshape local and global Ca2+ signal amplitudes and kinetics (Figure 1).
Voltage-dependent Ca2+ channels Ca2+ entry into excitable cells through voltage-dependent Ca2+ channels (VDCCs) is essential for membrane electrical activity and intracellular signal transduction. Many studies have focused on ROS modulation of VDCC activity. H2O2 has been shown to accelerate the overall channel opening process in neuronal P/Q-type Ca2+ channels expressed in Xenopus oocytes[8]. Studies in whole-cell-clamped guinea pig ventricular myocytes have shown that exogenous ROS suppresses L-type Ca2+ current[33]. Similarly, sulphydryl-oxidating agents, 2,2-dithiodipyridine and thimerosal, also inhibit the activity of rabbit smooth muscle L-type Ca2+ channels expressed in CHO cells[34], and it was found that free SH groups of L-type Ca2+ channels are essential for ROS modulation. Although the effects of H2O2 and other ROS on single DHPR channel activity have not been reported; previous studies indicate a ROS-induced decrease in this current of skeletal muscle[31]. In contrast, it has also been reported that H2O2 exerts no significant effect on L-type Ca2+ current in pancreatic b- cells[35]. In Arabidopsis guard cells, Pei and colleagues[36] identified a hyperpolarization-dependent Ca2+-permeable cation channel that is activated by H2O2.
Intracellular Ca2+ release channels The release of Ca2+ from the endo/sarcoplasmic reticulum (ER/SR) mediated by ryanodine receptors (RyR) and 1,4,5-inositol-triphosphate receptors (IP3R) is a primary Ca2+ signaling event. An RyR or IP3R channel is a homotetramer with each subunit containing many free cysteine residues that are susceptible to redox reaction by ROS. For instance, each of the four homologous 560 kDa RyR1 proteins contains approximately 50 free cysteine residues[37], and approximately 21 free cysteines per subunit of RyR2[38]. Changes in the redox state of RyR and IP3R would affect their activities. There are three types of RyR expressed in mammalian cells, known as RyR1, RyR2, and RyR3. RyR1 is the dominant isoform in skeletal muscle, RyR2 is found in high levels in cardiac muscle, and RyR3 is expressed at relatively low levels in many tissues including diaphragm and brain[39]. RyR1 channels, in vitro, were markedly activated by 100 mmol/L and 1 mmol/L H2O2 under redox potential clamp conditions[40]; were inhibited by 10 mmol/L H2O2[41]. Moreover, 3_5 mmol/L H2O2 directly modified the gating of sheep cardiac RyR2, resulting in an increase in channel open probability without affecting the conductance[33]. Similarly, H2O2 enhances Ca2+ release from SR in isolated ventricular myocytes. This effect is more prominent in cells previously dialyzed with low concentration thiol reductants, GSH (2 mmol/L) or dithiothreitol (DTT; 0.5 mmol/L)[42]. It is noteworthy that high concentration GSH (10 mmol/L) or DTT (2 mmol/L) itself strongly inhibits Ca2+ release in cardiomyocytes[42]. In neurons, activation of RyR3 by ROS might modify Ca2+-dependent long-term potentiation and long-term depression[37]. In the case of IP3R, it has been reported that O2·_ enhances IP3-induced Ca2+ release from fractionated vascular smooth muscle SR[43], and oxidized GSH induces Ca2+ release from IP3R in intact hepatocytes[44]. Moreover, the data reported by Hu et al[45] demonstrated that exogenous NADPH (substrate of NADPH oxidase) or H2O2 increases the sensitivity of intracellular Ca2+ stores to IP3 in human endothelial cells. Despite these advances, it remains to be convincingly demonstrated whether endogenous ROS can appropriately modify RyR and IP3R activity in intact cells.
Ca2+ pumps and Na+/Ca2+ exchanger Both the plasma membrane Ca2+-ATPases (PMCA) and the ER/SR Ca2+-ATPases (SERCA), as well as Na+/Ca2+ exchangers (NCX), are sensitive to ROS regulation. ROS can effectively inhibit Ca2+ transport by SERCA in smooth muscle cells[2] and depress cardiac sarcolemmal Ca2+-ATPase[46]. SERCA is more sensitive to ROS than PMCA is. For example, H2O2 and O2·_ can completely uncouple the hydrolytic reaction of PMCA and inhibit the hydrolytic reaction of SERCA[33]. Both stimulating and inhibiting regulation of ROS on NCX have been reported in isolated sarcolemmal vesicles and in intact cells. It has been proposed that H2O2 generated from the xanthine/xanthine oxidase system (X/XO) enhances NCX activity in ventricular myocytes, causing Ca2+ overload and triggering arrhythmia during reperfusion, because of the NCX pathological inverted running[47]. Similar results were obtained in sarcolemmal vesicles from bovine heart[48,49]. In contrast, oxidants from hypoxanthine/xanthine oxidase depress NCX activity in guinea pig ventricular myocytes under voltage-clamp conditions[50]. The exchanger activity is also inhibited by the oxidizing agent HOCl[48]. Although mitochondrial NCX and Ca2+ uniporter have been reported to participate in mitochondrial Ca2+ regulation[51], it is not yet clear how they are modulated by intramitochondrial ROS.
Other components of the Ca2+ signaling system that are modulated by ROS include store-operated Ca2+ channel[51], KCa channel[33,52], and CaM[8]. Taken together, ROS as intracellular signaling molecules might directly and indirectly modify components of Ca2+ signaling pathways, thus altering Ca2+ homeostasis and reshaping local and global Ca2+ signals.
Global Ca2+ signaling It has been widely accepted that exogenous ROS could induce dynamic changes in [Ca2+]c in a variety types of cells[54_59]. This effect might be due to mobilization of intracellular Ca2+ stores and to influx of extracellular Ca2+. As an important feature of the cross-regulation between ROS and Ca2+, the ROS effect on Ca2+ signaling can vary from stimulative to repressive, depending on the type of oxidants, their concentrations, and duration of exposure. When treated with 100 mmol/L H2O2, [Ca2+]c of rat cardiomyocytes increased markedly, and continued to rise after washout, whereas 1 mmol/L H2O2 had no effect on [Ca2+]c[58]. At an even higher dose, 1 mmol/L H2O2 elicits biphasic response in cardiac myocytes, a transient augmentation of Ca2+-induced Ca2+ release followed by a suppression of [Ca2+]c transient after 5 min exposure. The biphasic nature could be explained by a possible ER/SR depletion due to a combination of release enhancement and SERCA inhibition (Figure 1). Conversely, reducing agents such as GSH and DTT attenuate [Ca2+]c transients[3]. The effect of ROS on Ca2+ signaling is also tissue specific. For instance, it had been shown that H2O2 (100_300 mmol/L) activates contraction in skinned skeletal muscle fibers without producing an increase in [Ca2+]c[60]. Under pathological conditions, such as hypoxia and ischemia/reperfusion injury, mitochondria dysfunction results in ROS increase that mediates the following cytosolic Ca2+ overload[4,59] by triggering Ca2+ release from the ER through RyR[59] or from the external through PMCA[4].
Local Ca2+ signaling Ca2+ sparks[61] constitute the elementary Ca2+ releasing events and play an important role in local control of Ca2+ signaling in many types of cells. As is the case with ROS regulation of global Ca2+ signaling, ROS modulation of Ca2+ sparks occurs in a ROS species- and tissue-specific fashion. For example, O2·_ generated from X/XO elicits a slowly developing decrease of Ca2+ spark frequency down to 56% of control in permeabilized rat ventricular myocytes[62]. In contrast, mitochondria-derived ROS, generated from diazoxide (an ATP-sensitive K+ channel opener)- induced mitochondrial depolarization, elevates Ca2+ spark frequency and enhances the coupling of sparks to Ca2+-sensitve K+ channels in smooth muscle cells[63]. In permea-bilized rat skeletal muscle fibers, 50 mmol/L H2O2 was also found to increase Ca2+ spark frequency[64]. More direct evidence is needed to confirm the regulation of local and global Ca2+ signals by mitochondria-derived ROS in physiological and pathological conditions.
Concluding remarks
Cross-talk between Ca2+ and ROS signaling systems occurs at multiple levels in different subcellular compartments (eg, the plasma membrane, the cytosol and mitochondria), and involves a constellation of molecular players (Figure 1). The reciprocal interactions between Ca2+ and ROS signaling systems can be both stimulatory and inhibitory, depending on the type of target proteins, the ROS species, the dose, the time history, and the cell contexts. Both ROS generation and clearance as well as Ca2+ signaling are subject to tight local regulation, therefore future study should unravel endogenous high local or compartmentalized ROS (eg, inside the mitochondrial matrix, ER/SR lumen or nucleoplasm) interacting with Ca2+ signaling molecules, and vice versa. Such cross-talk provides not only a fine-tuning mechanism for homeostatic regulation of either system, but also a coupling mechanism for signaling integration in the regulation of physiological functions. Under pathophysiological conditions, however, abnormalities in either signaling system could propagate into the other system, and feedback reinforcement could cause instabilities in both systems. We eagerly await future investigations to enlighten us on the cell logic behind the complex bi-directional interactions of the two signaling systems.
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One of the most versatile and universal signalling agents in the human body is the calcium ion, Ca2+. How does this simple ion act during cell birth, life and death, and how does it regulate so many different cellular processes?
One of the most versatile and universal signalling agents in the human body is the calcium ion, Ca2+. How does this simple ion act during cell birth, life and death, and how does it regulate so many different cellular processes?