Acta Pharmacologica Sinica

Editorial

Acta Pharmacologica Sinica 2006 July; 27 (7): 767-772

Calcium signaling in physiology and pathophysiology

He-ping Cheng^1,4, Sheng WEI¹, Li-ping WEI², Alexei Verkhratsky^3,4

¹Institute of Molecular Medicine and State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Science, Peking University, Beijing 100871, China;²Center for Bioinformatics, College of Life Science, Peking University, Beijing 100871, China; ³Faculty of Life Sciences, the University of Manchester, Manchester M13 9PT, UK

Correspondence to Prof He-ping Cheng.
Phn/Fax 86-10-6276-5957.
E-mail chengp@pku.edu.cn
and Prof Alexei VERKHRATSKY.
Phn 44-161-275-5414.
Fax 44-161-275-5948.
E-mail alex.verkhratsky@manchester.ac.uk
Received 2006-05-22
Accepted 2006-05-22
doi: 10.1111/j.1745-7254.2006.00399.x

Abstract

Calcium ions are the most ubiquitous and pluripotent cellular signaling molecules that control a wide variety of cellular processes. The calcium signaling system is represented by a relatively limited number of highly conserved transporters and channels, which execute Ca²⁺ movements across biological membranes and by many thousands of Ca²⁺-sensitive effectors. Molecular cascades, responsible for the generation of calcium signals, are tightly controlled by Ca²⁺ ions themselves and by genetic factors, which tune the expression of different Ca²⁺-handling molecules according to adaptational requirements. Ca²⁺ ions determine normal physiological reactions and the development of many pathological processes.

Key words

Extract

Note: Please read the complete full text with Figures and Tables at
Ja, Kalzium das ist alles...
Otto Loewi
(1936 Nobel Laureate)

Experimental indications, demonstrating the role of calcium as a universal signalling molecule, controlling a huge variety of very different physiological functions appeared at the end of 19th century. First, Sydney Ringer showed that calcium ions were indispensable for fish survival, muscle contraction, the development of fertilized eggs and tadpole and for cells adhesion^[1_5]. Several years later, Locke^[6] and Overton^[7] demonstrated the critical importance of Ca²⁺ for signal transduction between nerve and muscle. The general theory of calcium as a universal second messenger, however, appeared half a century later, when Lewis Victor Heilbrunn concluded that "the reaction of this calcium with the protoplasm inside the cell is the most basic of all protoplasmic reactions"^[8]. This theory, although almost completely ignored at the time of its appearance, brilliantly withstood the test of time and experimental efforts (Figure 1), and today, the calcium signalling is generally regarded as the most ubiquitous and the most pluripotent system, involved in regulation of almost all known cellular processes^[9].
The universality of calcium as a signaling molecule is manifested on many levels. First, Ca²⁺ ions act as intracellular messengers throughout phylogenetic history, from early prokaryotes to eukaryotic cells.
Second, within every cell, Ca²⁺ exerts its action through several very different levels, which are executed in different spatial and temporal domains. Indeed, Ca²⁺ ions control localized processes, (eg, exocytosis) and global responses (eg, myocyte contraction) with equivalent efficacy and ease (Figure 2). Similarly, Ca²⁺-dependent cellular responses occur in an amazingly wide time scale, from microseconds (eg, activation of ion channels) to many hours, weeks, months or even years (eg, synaptic plasticity, memory, long-term adaptation or neuronal ageing).
Third, the Ca²⁺ signaling system is constructed with an incredible intrinsic versatility. The actual molecular cascades controlling Ca²⁺ movements through cellular membranes (Figure 3) are limited to several families of relatively similar pumps (plasmalemmal and intracellular PMCA, SERCA or SPCA^[10_12]), sodium-calcium exchangers (NCX, residing in plasmalemma or in mitochondria^[13,14]) and plasmalemmal^[15_18] and intracellular^[13,19_21] Ca²⁺ channels. Yet these cascades are very tightly regulated, which determines their great adaptability and versatility. Importantly, calcium signalling molecules are subject to a control by Ca²⁺ ions themselves: changes in Ca²⁺ gradients or local concentration control the availability of Ca²⁺ channels and regulate the activity of Ca²⁺ pumps^[22_24]. On a different level, the expression of various molecules, controlling Ca²⁺ movements is responsive to the changes in the environment, and therefore the combina- tions of calcium signaling molecules (or "Ca²⁺ signalling toolkits"^[25]) can be rapidly modified, thus adapting the system to the external demands.
Fourth, the effector part of the calcium signalling system, the Ca²⁺ sensors, is represented by thousands of proteins, which have different affinity to Ca²⁺ ions, with the dissociate constant spanning seven orders of magnitude (Figure 4), and different cellular location. This host of Ca²⁺ sensors determines the ubiquity and promiscuity of Ca²⁺ signaling: expression of specific Ca²⁺ sensors commands specific Ca²⁺-regulatory function (eg, expression of Ca²⁺-sensitive contractile in muscle cells determines the excitation contraction coupling), whereas different affinity/localization of Ca²⁺ sensors will allow precise regulation of very different processes within a single cell.
The specificity and precise localization of calcium signalling machinery is also supported by an existence of several intracellular compartments, characterized by a clearly distinct Ca²⁺ homeostasis. These compartments are represented by the cytosol, by endoplasmic reticulum (ER) and mitochondria. In the cytosol the concentration of free Ca²⁺ ([Ca²⁺]_i) is very low, approximately 50_100 nmol/L, which is achieved by continuous activity of Ca²⁺ extruding systems and by high-affinity cytosolic calcium buffers^[14,26,27]. As a consequence, activation of Ca²⁺ entry channels results in rapid elevation of [Ca²⁺]_i, yet the strong Ca²⁺ buffering favours localisation of Ca²⁺ signals and the creation of Ca²⁺ microdomains. This is very important for regulation of focal cellular responses, such as exocytosis^[28,29].
The ER, in contrast, provides for a very different Ca²⁺ handling environment. The intra-ER, or intraluminal free Ca²⁺ concentration ([Ca²⁺]_L), is set at a rather high level, 100_800 µmol/L^[30_36], which is achieved by a continuous activity of SERCA pumps. In addition, the affinity of intra-ER Ca²⁺ buffers is rather low, being in the range of 0.5_1.0 mmol/L, which favours Ca²⁺ diffusion through the continuous ER lumen. The latter therefore forms a nanoscopic "Ca²⁺ tunnel", which allows long-range Ca²⁺ transport in polarised cells^[37_40]. Importantly, numerous intra-ER Ca²⁺-dependent enzymatic systems require high (>50 µmol/L) [Ca²⁺]_L for normal functioning^[41,42]. The ER acts as a very powerful intracellular signalling organelle, which integrates various incoming signals with cellular biochemistry (through regulation of protein synthesis and posttranslational folding). Furthermore, the ER produces numerous output signals, which regulate cell function and determine adaptive responses. Particularly important is the role of ER in the generation of cytoplasmic Ca²⁺ signals because the ER acts as a dynamic Ca²⁺ store able to rapidly release Ca²⁺ through intracellular Ca²⁺ channels^[19,21] and to terminate Ca²⁺ signals through SERCA-dependent Ca²⁺ pumping. As a consequence, the ER appears simultaneously as a source and sink for [Ca²⁺]_i^[43_45], while the balance between Ca²⁺ release and Ca²⁺ uptake is regulated by [Ca²⁺]_L and [Ca²⁺]_i dynamics in a vicinity of Ca²⁺ release channels^[46,47].
The third intracellular compartment with specific Ca²⁺ homeostasis is represented by mitochondria, which are able to accumulate (via Ca²⁺ uniporter) and release (via Na⁺/Ca²⁺ exchanger) Ca^{2+
[13]}. Mitochondrial Ca²⁺ signalling links cellular activity to ATP production and ROS metabolism; in addition mitochondria can participate in [Ca²⁺]_i regulation, especially in pathological conditions^[48_50].
Finally, the signalling system mediated by Ca²⁺ ions operates in two modes: the digital and analogue. The digital mode is determined by a discrete character of Ca²⁺ entry through the membrane, which is controlled by opening and closing of Ca²⁺ permeable channels. Yet, when inside the intracellular compartments, Ca²⁺ ions diffuse, and they diffuse with a different velocity and anisotropy, thus creating a complex concentration gradients, which represents an analogue signalling, coded in amplitude, space and time.
All these features make the Ca²⁺ signaling system absolutely unique among other cellular signaling pathways. Ca²⁺ ions are fundamentally different from other signalling molecules in a sense that they are subjected to neither catabolism nor anabolism; they can be merely bound to calcium buffers or accumulated into Ca²⁺ stores, yet they remain readily available for mobilisation. This makes the signalling system quite economical. Huge Ca²⁺ gradients, existing between extracellular space, intracellular organelles and the cytoplasm contribute to an exceedingly high signal-to-noise ratio of the whole signalling system. Further, the promiscuity of Ca²⁺ ions as intracellular messengers provides for a remarkable versatility; the variety of Ca²⁺ sensor proteins together with temporal and spatial heterogeneity of Ca²⁺ fluctuations, make the signalling system both context and history-specific. As a consequence, Ca²⁺ ions often play very opposite effects even within the same cell. One of the best examples of such a dualism exists in arterial smooth muscle cells, where subsurface calcium sparks relax the myocyte by activating Ca²⁺-dependent K⁺ channels^[51_53], whereas global calcium signals trigger cell contraction.
Not surprisingly, the omnipotence of Ca²⁺ signaling makes it an important player not only in normal conditions but also in pathological cellular reactions. Here the dualism of Ca²⁺ ions transpires even more illustriously, as indeed Ca²⁺ ions are the ions of life and death. Depriving the cells from Ca²⁺ ions by the removal of extracellular Ca²⁺, or artificial chelating of intracellular Ca²⁺, or depletion of cellular free Ca²⁺, all of these interventions result in rapid and inevitable cell death^[42,54]. At the same time excess of Ca²⁺ is absolutely toxic, and cell death from Ca²⁺ overload represents probably the most general mechanism of cell demise^[55,56]. Similarly, chronic disruptions of Ca²⁺ homeostatic machinery may cause development of various diseases, such as ischemic-induced cell death^[57_63], neurodegeneration^[42,54,64], heart failure^[65,66] or underlying cognitive deficits in senescence^[67_69].
When compiling this special issue we tried to cover all of the important parts of calcium signaling machinery and its role in physiology and disease. We hope that this collection of articles will spark further interest in various aspects of Ca²⁺ and inspire further developments into the functions and importance of this truly magnificent ion of life.

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