Calcium signalling: Past, present and future

FEBS Journal, 2009

Calcium ions (Ca 2+) control and influence a diverse array of cellular processes such as muscle contraction, gene expression, energy metabolism, proliferation and cell death. In order to extensively control cellular activity, it is necessary to regulate Ca 2+ signals (changes in Ca 2+ concentration) in 3D space, time and amplitude. Cells normally maintain a low resting 'free' Ca 2+ concentration in the cytosol ([Ca 2+ ] c) of 100 nm. This contrasts with 1 mm in the extracellular fluid of terrestrial animals and 10 mm in seawater. In order to achieve this low resting [Ca 2+ ] c , cells remove Ca 2+ using two energy-dependent mechanisms. First, plasma membrane Ca 2+ ATPases (PMCA) pump Ca 2+ out of the cell against a concentration gradient, consuming ATP in the process. Second, the Na +-Ca 2+ exchanger (NCX) uses the electrochemical Na + gradient; one Ca 2+ being extruded for every three Na + ions entering. In addition, eukaryotic cells can sequester Ca 2+ into intracellular organelles, in particular the endoplasmic reticulum (ER). Organellar Ca 2+ sequestration requires either ATP hydrolysis or a favourable electrochemical gradient. Ca 2+ channels in the plasma membrane or release channels on Ca 2+-containing organelles help deliver Ca 2+ to the required cellular location. This enables the generation of Ca 2+ signals that can be small or large in amplitude, restricted to a small microdomain or global across the cell. Ca 2+ signals can be of variable duration lasting from a few milliseconds to many hours (Fig. 1A). They can either be simple Ca 2+ elevations or

Nature, 1998

Current biology, 2002

Recent studies have expanded the number of channel types and messengers that lead to Ca 2+ signals within cells. Furthermore, we are beginning to understand the complex interplay between different sources of Ca 2+ .

Frontiers in Physiology, 2023

Cytosolic Ca 2+ signals are organized in complex spatial and temporal patterns that underlie their unique ability to regulate multiple cellular functions. Changes in intracellular Ca 2+ concentration ([Ca 2+ ] i) are finely tuned by the concerted interaction of membrane receptors and ion channels that introduce Ca 2+ into the cytosol, Ca 2+-dependent sensors and effectors that translate the elevation in [Ca 2+ ] i into a biological output, and Ca 2+-clearing mechanisms that return the [Ca 2+ ] i to prestimulation levels and prevent cytotoxic Ca 2+ overload. The assortment of the Ca 2+ handling machinery varies among different cell types to generate intracellular Ca 2+ signals that are selectively tailored to subserve specific functions. The advent of novel high-speed, 2D and 3D time-lapse imaging techniques, single-wavelength and genetic Ca 2+ indicators, as well as the development of novel genetic engineering tools to manipulate single cells and whole animals, has shed novel light on the regulation of cellular activity by the Ca 2+ handling machinery. A symposium organized within the framework of the 72nd Annual Meeting of the Italian Society of Physiology, held in Bari on 14-16th September 2022, has recently addressed many of the unexpected mechanisms whereby intracellular Ca 2+ signalling regulates cellular fate in healthy and disease states. Herein, we present a report of this symposium, in which the following emerging topics were discussed: 1) Regulation of water reabsorption in the kidney by lysosomal Ca 2+ release through Transient Receptor Potential Mucolipin 1 (TRPML1); 2) Endoplasmic reticulum-to-mitochondria Ca 2+ transfer in Alzheimer's disease-related astroglial dysfunction; 3) The non-canonical role of TRP Melastatin 8 (TRPM8) as a Rap1A inhibitor in the definition of some cancer hallmarks; and 4) Non-genetic optical stimulation of Ca 2+ signals in the cardiovascular system.

Proceedings of the National Academy of Sciences, 2002

An experiment performed in London nearly 120 years ago, which by today's standards would be considered unacceptably sloppy, marked the beginning of the calcium (Ca 2+ ) signaling saga. Sidney Ringer [Ringer, S. (1883) J. Physiol. 4, 29–43] was studying the contraction of isolated rat hearts. In earlier experiments, Ringer had suspended them in a saline medium for which he admitted to having used London tap water, which is hard: The hearts contracted beautifully. When he proceeded to replace the tap water with distilled water, he made a startling finding: The beating of the hearts became progressively weaker, and stopped altogether after about 20 min. To maintain contraction, he found it necessary to add Ca 2+ salts to the suspension medium. Thus, Ringer had serendipitously discovered that Ca 2+ , hitherto exclusively considered as a structural element, was active in a tissue that has nothing to do with bone or teeth, and performed there a completely novel function: It carried th...

Seminars in Cell and Developmental Biology, 2001

Calcium (Ca 2+ ) is an almost universal intracellular mes- senger, controlling a diverse range of cellular processes, such as gene transcription (see Mellstrom and Naranjo, this issue), muscle contraction and cell proliferation. The ...

Plant Signaling & Behavior, 2009

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.

European journal of pharmacology, 2002

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...

Cell Calcium, 2000

Ca 2+ is a very important signaling molecule within cells . Many cellular functions are directly or indirectly regulated by the free cytosolic Ca 2+ concentration ([Ca 2+ ] i ). The [Ca 2+ ] i must be very tightly regulated in time, in space and in amplitude because cells manage to extract specific information from these three parameters. Because Ca 2+ is such an important signaling molecule, mutations causing drastic functional changes in intracellular Ca 2+ homeostasis are most likely not compatible with life [2]. Mutations or abnormalities in one of the various proteins involved in intracellular Ca 2+ regulation, which in vitro seem only to induce trivial alterations in the function of the protein, often lead to a plethora of diseases .

European Journal of Biochemistry, 1990

The Journal of Experimental Biology, 1997

The secretion of ions and fluid plays a critical role in a variety of physiological activities that are vital to homeostatic mechanisms in animals. Control of such secretory activity is achieved by a range of neurotransmitters and hormones many of which act intracellularly by generating the second messenger inositol 1,4,5-trisphosphate (InsP3) and increasing cytosolic free calcium ion concentrations ([Ca 2+ ]i). These increases are achieved by a combination of the InsP3-induced release of Ca 2+ from specific intracellular stores and the activation of Ca 2+ entry from the extracellular environment. The [Ca 2+ ]i signal represents a balance between the adequate activation of components of the secretory mechanism and the avoidance of [Ca 2+ ]i levels that are toxic to the cell. Resting [Ca 2+ ]i is maintained low by the action of Ca 2+ pumps on the intracellular stores and plasma membrane, with the result that gradients for Ca 2+ movement into the cytosol from either of these two sources are very large and there is considerable potential for achieving rapid increases in [Ca 2+ ]i. Consequently, for successful Ca 2+ signalling, it is imperative that these two mechanisms of raising [Ca 2+ ]i (i.e. Ca 2+ release and Ca 2+ entry) are closely integrated. Current models emphasize the activation of Ca 2+ entry as a downstream result of the emptying of the intracellular stores ('capacitative' model). Whilst this may be true for situations of maximal stimulation, recent experiments on the oscillatory [Ca 2+ ]i responses typical of more physiological levels of stimulation indicate a previously unsuspected, independent activation of Ca 2+ entry involving arachidonic acid. This arachidonic-acid-activated entry plays a key role, along with InsP3, in inducing the repetitive release of Ca 2+ from the stores to produce the [Ca 2+ ]i oscillations. In this way, the two components responsible for the elevation of [Ca 2+ ]i are intimately related and their dual effects closely coordinated, resulting in the finely tuned control of agonistinduced changes in [Ca 2+ ]i.

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.

General Physiology and Biophysics

Postsynaptic potential is only one aspect of extensive communication between neurons and their synapses. Besides generating of potential changes by activation of ionic channels, neurotransmitters may activate receptors linked with the transient concentration changes of one or several intracellular second messengers, including calcium ions (Ca2+). In the neuronal cells calcium triggers and controls specific processes. Transient changes of Ca2+ concentration within the cell play an important signal role by coupling electrical and chemical impulses generated on the plasma membrane with the intracellular systems of responses. Several proteins and/or protein complexes, whose functions are directly controlled by calcium, have been identified in the neuronal cells. Their biochemical properties and physiological importance as well as cellular localization are discussed in this paper.