Intracellular Calcium Homeostasis and Signaling

Progress in Biophysics and Molecular Biology, 2016

The aim of the study was to determine the correlations between intracellular calcium ion level and a cell's ability to survive. The intracellular concentration of Ca 2þ ions, maintained through different mechanisms, plays an important role in signalling in cells. The deregulation of these mechanisms by various cell stressors (e.g. cytotoxic agents) can disturb Ca 2þ homeostasis and influence Ca 2þ-dependent signalling pathways in the cell. Perturbations of intracellular electrochemical equilibrium may lead to changes in cell function or even to cell death. According to some experimental results, one of the cell stressors may be exposure to magnetic fields (MF). Because of the wide distribution of MF sources in our environment, magnetic fields have recently been intensively examined in relation to the occurrence of cancer. Nevertheless, two questions still remain unanswered: Is the influence of MF on cells positive or negative, and what mechanism(s) underlie the effects of MF action on cells? Most studies focus on the influence of MF on Ca 2þ ion fluxes as calcium ions play the role of intracellular second messengers, triggering many signalling cascades. Physical models assuming the mechanisms generating the disturbance of ionic transport and/or the dysfunction of ioneprotein complexes in cells due to MF action have been widely discussed in the literature, but a detailed explanation of experimental results is still awaited. The dynamics of the concentration of intracellular calcium ions can be detected by various methods, including optical and non-optical techniques. This review combines an insight into basic intracellular Ca 2þ regulative mechanisms and common techniques used to detect changes in Ca 2þ concentration inside the cell. The emphasis here is on the determination of Ca 2þ regulative mechanisms developed in non-excitable cells (e.g. U937 cells, HeLa, etc.), which are probably mainly involved in cell responses to external stress (e.g. MF stimuli).

Journal of Cell Science, 2010

Commentary Intracellular Ca 2+ signals are central to practically all aspects of cellular physiology, including secretion, contraction, fertilization, synaptic transmission, cell division and gene expression. The fact that Ca 2+ signals mediate disparate cellular responses, often in the same cell, necessitates a high level of specificity and versatility. Specificity is encoded by the spatial and temporal features of the Ca 2+ signal itself, and by the sensitivity, availability and localization of downstream Ca 2+ -dependent effectors . In addition, the astounding temporal (microseconds to hours) and concentration (nanomolar to millimolar) ranges across which Ca 2+ acts contribute to its versatility and specificity as an effective signaling module Clapham, 2007).

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.

F1000Research, 2016

Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca2+ exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca2+ changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca2+ are controlled not only by the frequency of Ca2+ oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca2+ stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca2+ oscillations. The main characteristics of the Ca2+ exchange fluxes with these compartments are also reviewed.

Science China-life Sciences, 2011

Annals of the New York Academy of Sciences, 1988

bioRxiv (Cold Spring Harbor Laboratory), 2022

The level of cytosolic calcium (Ca 2+) in cells is tightly regulated to about 100 nM (pCa ≈ 7). Due to external stimuli, the basal cytosolic Ca 2+ level can temporarily be raised to much higher values. The resulting Ca 2+ transients take part in cell-intrinsic signals, which result in cellular responses. Because of its signaling importance and that high levels of Ca 2+ can lead to apoptosis, regulation and homeostatic control of cytosolic Ca 2+ is essential. Based on experimentally known molecular interactions and kinetic data together with control theoretic concepts (integral feedback) we developed a basic computational model describing robust cytosolic Ca 2+ homeostasis. The aim of the model is to describe the integrative mechanisms involved in cytosolic Ca 2+ homeostasis in non-excitable cells. From a model perspective, the cytosolic steady state value (set point) of 100 nM is determined by negative feedback loops (outflow controllers), one of these represented by the plasma membrane Ca 2+ ATPase (PMCA)-calmodulin (CaM) pump and its activation by cytosolic Ca 2+. Hysteretic behaviors of the Ca pumps and transporters have been added leading to improved kinetic behaviors indicating that hysteretic properties of the Ca 2+ pumps appear important how cytosolic Ca 2+ transients are formed. Supported by experimental data the model contains new findings that the activation of the inositol 1,4,5,-tris-phosphate receptor by cytosolic Ca 2+ has a cooperativity of 1, while increased Ca 2+ leads to a pronounced inhibition with a cooperativity of 2. The model further suggests that the capacitative inflow of Ca 2+ into the cytosol at low Ca 2+ storage levels in the ER undergoes a successive change in the cooperativity of the Store Operated calcium Channel (SOCC) as Ca 2+ levels in the ER change. Integrating these aspects the model can show sustained oscillations with period lengths between 2 seconds and 30 hours.

Physiological Reviews, 2006

Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different intracellular actions, ranging from contraction to secretion, from proliferation to cell death. The key to this pleiotropic role is the complex spatiotemporal organization of the [Ca2+] rise evoked by extracellular agonists, which allows selected effectors to be recruited and specific actions to be initiated. In this review, we discuss the structural and functional bases that generate the subcellular heterogeneity in cellular Ca2+levels at rest and under stimulation. This complex choreography requires the concerted action of many different players; the central role is, of course, that of the calcium ion, with the main supporting characters being all the entities responsible for moving Ca2+between different compartments, while the cellular architecture provides a determining framework within w...

Biochemistry and Molecular Biology Education, 2008

Cell signaling is an essential process in which a variety of external signals, defined as first messengers, are translated inside the cells into specific responses, which are mediated by a less numerous group of second messengers. The exchange of signals became a necessity when the transition from monocellular to pluricellular life brought with it the division of labor among the cells of the organisms: unicellular organisms do not depend on the mutual exchange of signals, as they essentially only compete with each other for nutrients. Calcium (Ca2+) was selected during evolution as second messenger, because its chemistry made it a much more flexible ligand than the other abundant cations in the primordial environment (Na+, K+, Mg2+). Ca2+ can accept binding sites of irregular geometries and is thus ideally suited to be a carrier of biological information. The Ca2+ signal has properties that set it apart from those of all other biological messengers: they will be reviewed in this contribution. Among them, the ambivalent character of the Ca2+ signal is the most important: while essential to the viability of the cells, it can also easily become a conveyor of doom.

Physiological Reviews, 1994