Calcium: a life and death signal
Martin Bootman1998, Nature
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Abstract
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Calcium ions (Ca2+) play a crucial role in a wide range of cellular processes, acting as intracellular messengers that regulate activities such as movement, heartbeat, and memory formation. This signaling is facilitated through localized and global Ca2+ signals derived from both external sources and internal stores, allowing different cell types to tailor the signals to their physiological needs. Recent advances in imaging technology have enhanced the understanding of the spatio-temporal properties of these signals, which are foundational to cellular functions including fertilization, muscle contraction, and apoptosis.
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FEBS Journal, 2009
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Fundamental properties of Ca2+ signals
Biochimica et Biophysica Acta (BBA) - General Subjects, 2012
Spatiotemporal dynamics of Ca2+ signaling and its physiological roles
Proceedings of The Japan Academy Series B-physical and Biological Sciences, 2010
Changes in the intracellular Ca 2þ concentration regulate numerous cell functions and display diverse spatiotemporal dynamics, which underlie the versatility of Ca 2þ in cell signaling. In many cell types, an increase in the intracellular Ca 2þ concentration starts locally, propagates within the cell (Ca 2þ wave) and makes oscillatory changes (Ca 2þ oscillation). Studies of the intracellular Ca 2þ release mechanism from the endoplasmic reticulum (ER) showed that the Ca 2þ release mechanism has inherent regenerative properties, which is essential for the generation of Ca 2þ waves and oscillations. Ca 2þ may shuttle between the ER and mitochondria, and this appears to be important for pacemaking of Ca 2þ oscillations. Importantly, Ca 2þ oscillations are an efcient mechanism in regulating cell functions, having eects supra-proportional to the sum of duration of Ca 2þ increase. Furthermore, Ca 2þ signaling mechanism studies have led to the development of a method for specic inhibition of Ca 2þ signaling, which has been used to identify hitherto unrecognized functions of Ca 2þ signals.
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Seminars in Cell & Developmental Biology, 2012
The ability of Ca(2+), the simplest of all intracellular messengers, selectively to regulate so many cellular behaviours is due largely to the complex spatiotemporal organization of intracellular Ca(2+) signals. Most signalling pathways, including those that culminate in Ca(2+) signals, comprise sequences of protein-protein interactions linked by diffusible messengers. Using specific examples to illustrate key principles, we consider the roles of both components in defining the spatial organization of Ca(2+) signals. We discuss evidence that regulation of most Ca(2+) channels by Ca(2+) contributes to controlling the duration of Ca(2+) signals, to signal integration and, via Ca(2+)-induced Ca(2+) release, to defining the spatial spread of Ca(2+) signals. We distinguish two types of protein-protein interaction: scaffolds that allow rapid local transfer of diffusible messengers between signalling proteins, and interactions that directly transfer information between signalling proteins. Store-operated Ca(2+) entry provides a ubiquitous example of the latter, and it serves also to illustrate how Ca(2+) signals can be organized at different levels of spatial organization - from interactions between proteins to interactions between organelles.
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Current Biology, 1996
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Mathematical Biosciences, 2006
Calcium (Ca 2+ ) oscillations play fundamental roles in various cell signaling processes and have been the subject of numerous modeling studies. Here we have implemented a general mathematical model to simulate the impact of store-operated Ca 2+ entry on intracellular Ca 2+ oscillations. In addition, we have compared two different models of the inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) and their influences on intracellular Ca 2+ oscillations. Store-operated Ca 2+ entry following Ca 2+ depletion of endoplasmic reticulum (ER) is an important component of Ca 2+ signaling. We have developed a phenomenological model of store-operated Ca 2+ entry via store-operated Ca 2+ (SOC) channels, which are activated upon ER Ca 2+ depletion. The depletion evokes a bi-phasic Ca 2+ signal, which is also produced in our mathematical model. The IP 3 R is an important regulator of intracellular Ca 2+ signals. This IP 3 sensitive Ca 2+ channel is also regulated by Ca 2+ . We apply two IP 3 R models, the Mak-McBride-Foskett model and the De Young and Keizer model, with significantly different channel characteristics. Our results show that the two separate IP 3 R models evoke intracellular Ca 2+ oscillations with different frequencies and amplitudes. Store-operated Ca 2+ entry affects the oscillatory behavior of these intracellular Ca 2+ oscillations. The IP 3 threshold is altered when store-operated Ca 2+ entry is excluded from the model. Frequencies and amplitudes of intracellular Ca 2+ oscillations are also altered without store-operated Ca 2+ entry. Under certain 0025-5564/$ -see front matter Ó (H. Brismar).
Imaging Ca2+ Entering the Cytoplasm through a Single Opening of a Plasma Membrane Cation Channel
The Journal of General Physiology, 1999
Discrete localized fluorescence transients due to openings of a single plasma membrane Ca 2 ϩ permeable cation channel were recorded using wide-field digital imaging microscopy with fluo-3 as the Ca 2 ϩ indicator. These transients were obtained while simultaneously recording the unitary channel currents using the whole-cell current-recording configuration of the patch-clamp technique. This cation channel in smooth muscle cells is opened by caffeine (Guerrero, A., F.S. Fay, and J.J. Singer. 1994. J. Gen. Physiol. 104:375-394). The localized fluorescence transients appeared to occur at random locations on the cell membrane, with the duration of the rising phase matching the duration of the channel opening. Moreover, these transients were only observed in the presence of sufficient extracellular Ca 2 ϩ , suggesting that they are due to Ca 2 ϩ influx from the bathing solution. The fluorescence transient is characterized by an initial fast rising phase when the channel opens, followed by a slower rising phase during prolonged openings. When the channel closes there is an immediate fast falling phase followed by a slower falling phase. Computer simulations of the underlying events were used to interpret the time course of the transients. The rapid phases are mainly due to the establishment or removal of Ca 2 ϩ and Ca 2 ϩ -bound fluo-3 gradients near the channel when the channel opens or closes, while the slow phases are due to the diffusion of Ca 2 ϩ and Ca 2 ϩ -bound fluo-3 into the cytoplasm. Transients due to short channel openings have a "Ca 2 ϩ sparklike" appearance, suggesting that the rising and early falling components of sparks (due to openings of ryanodine receptors) reflect the fast phases of the fluorescence change. The results presented here suggest methods to determine the relationship between the fluorescence transient and the underlying Ca 2 ϩ current, to study intracellular localized Ca 2 ϩ handling as might occur from single Ca 2 ϩ channel openings, and to localize Ca 2 ϩ permeable ion channels on the plasma membrane.
On Ca2+ signalling research
Science China Life Sciences, 2012
As a highly versatile intracellular signal, calcium (Ca 2+) regulates many different cellular processes in both animal and plant systems. Disruption of Ca 2+ homeostasis contributes to several human diseases. Owing to the importance of Ca 2+ signalling, its research is now an active field in life science. There are numerous Ca 2+ signalling systems, consisting of a diverse array of signalling units that deliver Ca 2+ signals with different spatial and temporal properties [1,2], playing roles in ubiquitous biological processes including gene regulation, fuel generation, substance transport, hormone and neurotransmitter secretion, cell motility and muscle contraction [3]. Consequently, exquisite homeostasis of Ca 2+ cycling is the key for health of humans, the disruption of which is related to many human diseases such as heart failure, neuron-degeneration, and diabetes [46]. Many remarkable achievements have greatly enhanced our understanding of Ca 2+ signaling, including those from Chinese scientists [710]. The 17th International Symposium on Ca 2+-binding Proteins and Ca 2+ Function in Health and Disease was held in Beijing, China, on July 16-20, 2011 [11], accompany which, a special issue of Science China Life Sciences was published for transducing Ca 2+ signals to effectors. The first part focused on the mechanisms in maintaining a low cytosolic level of Ca 2+ , with two articles reviewing the properties of the plasma membrane calcium ATPases (PMCA) in ejecting Ca 2+ into the extracellular space. First, Carafoli [12] reviewed the role of the plasma membrane calcium pump, PMCA2, in the hearing process. As an im-Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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Biophysical Journal, 2001
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The organisation and functions of local Ca(2+) signals
Journal of cell science, 2001
Calcium (Ca(2+)) is a ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation. The ability of a simple ion such as Ca(2+) to play a pivotal role in cell biology results from the facility that cells have to shape Ca(2+) signals in space, time and amplitude. To generate and interpret the variety of observed Ca(2+) signals, different cell types employ components selected from a Ca(2+) signalling 'toolkit', which comprises an array of homeostatic and sensory mechanisms. By mixing and matching components from the toolkit, cells can obtain Ca(2+) signals that suit their physiology. Recent studies have demonstrated the importance of local Ca(2+) signals in defining the specificity of the interaction of Ca(2+) with its targets. Furthermore, local Ca(2+) signals are the triggers and building blocks for larger global signals that propagate throughout cells.
From puffs to global Ca2+ signals: How molecular properties shape global signals
Chaos
The universality of Ca 2+ as second messenger in living cells is achieved by a rich spectrum of spatiotemporal cellular concentration dynamics. Ca 2+ release from internal storage compartments plays a key role in shaping cytosolic Ca 2+ signals. Deciphering this signaling mechanism is essential for a deeper understanding of its physiological function and general concepts of cell signaling. Here, we review recent experimental findings demonstrating the stochasticity of Ca 2+ oscillations and its relevance for modeling Ca 2+ dynamics. The stochasticity arises by the hierarchical signal structure that carries molecular fluctuations of single channels onto the level of the cell leading to a stochastic medium as theoretically predicted. The result contradicts the current opinion of Ca 2+ being a cellular oscillator. We demonstrate that cells use array enhanced coherence resonance to form rather regular spiking signals and that the "oscillations" carry information despite the involved stochasticity. The knowledge on the underlying mechanism also allows for determination of intrinsic properties from global observations. In the second part of the paper, we briefly survey different modeling approaches with regard to the experimental results. We focus on the dependence of the standard deviation on the mean period of the oscillations. It shows that limit cycle oscillations cannot describe the experimental data and that generic models have to include the spatial aspects of Ca 2+ signaling.
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ABSTRACT
Membrane ion channels as physiological targets for local Ca2+ signalling
Journal of Microscopy, 1999
Ionized calcium plays a central role as a second messenger in a number of physiologically important processes determining smooth muscle function. To regulate a wide range of cellular activities the mechanisms of subcellular calcium signalling should be very diverse. Recent progress in development of visible light-excitable¯uorescent dyes with high af®nity for Ca 2 (such as oregon green 488 BAPTA indicators,¯uo-3 and fura red) and confocal laser scanning microscopy provides an opportunity for direct visualization of subcellular Ca 2 signalling and reveals that many cell function are regulated by the microenvironment within small regions of the cytoplasm (`local control' concept). Here confocal imaging is used to measure and locate changes in [Ca 2 ] i on a subcellular level in response to receptor stimulation in visceral myocytes. We show that stimulation of muscarinic receptors in ileal myocytes with carbachol leading to activation of inositol 1,4,5-trisphosphate receptors (IP 3 Rs) accelerates the frequency of spontaneous calcium sparks (discharged via ryanodine receptors, RyRs) and gives rise to periodic propagating Ca 2 waves oscillating with a frequency similar to that of carbacholactivated cationic current oscillations. Furthermore, by combining the whole-cell patch clamp technique with simultaneous confocal imaging of [Ca 2 ] i in voltage-clamped vascular myocytes we demonstrate that calcium sparks may lead to the opening of either Ca 2-activated Cl À channels or Ca 2-activated K channels, and the discharge of a spontaneous transient inward current (STIC) or a spontaneous transient outward current (STOC), respectively.
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Intercellular Ca2+ Waves: Mechanisms and Function
Physiological Reviews, 2012
Intercellular calcium (Ca2+) waves (ICWs) represent the propagation of increases in intracellular Ca2+ through a syncytium of cells and appear to be a fundamental mechanism for coordinating multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca2+ from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra- and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiol...
Transformation of local Ca2+ spikes to global Ca2+ transients: the combinatorial roles of multiple Ca2+ releasing messengers
The EMBO Journal, 2002
In pancreatic acinar cells, low, threshold concentrations of acetylcholine (ACh) or cholecystokinin (CCK) induce repetitive local cytosolic Ca 2+ spikes in the apical pole, while higher concentrations elicit global signals. We have investigated the process that transforms local Ca 2+ spikes to global Ca 2+ transients, focusing on the interactions of multiple intracellular messengers. ACh-elicited local Ca 2+ spikes were transformed into a global sustained Ca 2+ response by cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP), whereas inositol 1,4,5-trisphosphate (IP 3 ) had a much weaker effect. In contrast, the response elicited by a low CCK concentration was strongly potentiated by IP 3 , whereas cADPR and NAADP had little effect. Experiments with messenger mixtures revealed a local interaction between IP 3 and NAADP and a stronger global potentiating interaction between cADPR and NAADP. NAADP strongly amp-li®ed the local Ca 2+ release evoked by a cADPR/IP 3 mixture eliciting a vigorous global Ca 2+ response. Different combinations of Ca 2+ releasing messengers can shape the spatio-temporal patterns of cytosolic Ca 2+ signals. NAADP and cADPR are emerging as key messengers in the globalization of Ca 2+ signals.
From puffs to global Ca[sup 2+] signals: How molecular properties shape global signals
Chaos: An Interdisciplinary Journal of Nonlinear Science, 2009
The universality of Ca 2+ as second messenger in living cells is achieved by a rich spectrum of spatiotemporal cellular concentration dynamics. Ca 2+ release from internal storage compartments plays a key role in shaping cytosolic Ca 2+ signals. Deciphering this signaling mechanism is essential for a deeper understanding of its physiological function and general concepts of cell signaling. Here, we review recent experimental findings demonstrating the stochasticity of Ca 2+ oscillations and its relevance for modeling Ca 2+ dynamics. The stochasticity arises by the hierarchical signal structure that carries molecular fluctuations of single channels onto the level of the cell leading to a stochastic medium as theoretically predicted. The result contradicts the current opinion of Ca 2+ being a cellular oscillator. We demonstrate that cells use array enhanced coherence resonance to form rather regular spiking signals and that the "oscillations" carry information despite the involved stochasticity. The knowledge on the underlying mechanism also allows for determination of intrinsic properties from global observations. In the second part of the paper, we briefly survey different modeling approaches with regard to the experimental results. We focus on the dependence of the standard deviation on the mean period of the oscillations. It shows that limit cycle oscillations cannot describe the experimental data and that generic models have to include the spatial aspects of Ca 2+ signaling.
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