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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Ca2+-Regulated Processes

Correspondence to James W. Putney, Jr., Calcium Regulation Section, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences—National Institutes of Health, P.O. Box 12233, Research Triangle Park, North Carolina 27709-2203.

Ca2+ is required for acute cellular responses, such as contraction or secretion

Sydney Ringer is credited with the first appreciation of the role of calcium as a regulator of cell function. He discovered that frog hearts beat longer in vitro if the saline solutions are made from “hard” water rather than from distilled water, and with this observation the role of Ca2+ in excitation—contraction coupling was discovered (see Chap. 43). Subsequently, Ca2+ was found to act as a signal for a myriad cellular responses, for example, secretion and changes in cell metabolism. Ca2+ is the major component of the signaling pathways that regulate epithelial cell secretion, including both discharge of proteins and regulation of transepithelial secretion of salts and water, and carbohydrate metabolism in the liver, including both glycogenolysis and gluconeogenesis (see Chaps. 31 and 42). In blood cells, various functions are subtended by PI-PLC-dependent [Ca2+]i signaling, including secretion and chemotaxis. Ca2+ mediates the shortening of muscle by interacting with specific calcium-binding proteins; in fast skeletal muscle, this is troponin, leading to disinhibition of the myosin ATPase (see Chap. 43). In other muscle types, regulation of the phosphorylation of myosin light chain is mediated by calcium. In virtually all cases, the initial target of calcium is a specific calcium-binding protein, the most extensively characterized of which is calmodulin (see Chap. 22) [18]. Calmodulin was discovered as a Ca2+-dependent regulator of cyclic nucleotide phosphodiesterase [18]. This protein now is recognized to be the most ubiquitous Ca2+-sensing protein, found in all eukaryotic organisms including yeasts. Calmodulin has four binding sites for Ca2+ with dissociation constants in the 1 to 10 μM range. The binding of Ca2+ induces a conformational change which imparts signaling information to a number of different molecules, including protein kinases and phosphatases.

Ca2+ also plays a role in more prolonged cellular events, such as mitogenesis and apoptosis

Throughout the life span of organisms, cells make decisions about growth, division, function and death. Following mitosis, a cell must either commit to re-enter the cell cycle or exit into Go, a quiescent state in which a differentiated function is maintained (see Chap. 27). In many, but not all, cell types, such cells may at a later time and with an appropriate stimulus re-enter the cell cycle to divide further. In circumstances in which a particular cell function is no longer needed, as in the case of the thymus, systemic signals may instruct cells to undergo a complex process of self-digestion and packaging, termed apoptosis [19]. Mutations in key genes that control mitogenesis can lead to inappropriate cell division or cancers; these are proto-oncogenes, and the transforming forms of the genes are oncogenes. It is noteworthy, although perhaps not unexpected, that the vast majority of proto-oncogenes code for proteins involved in signal-transduction pathways. One proto-oncogene, Bcl-2, acts as a suppressor of apoptosis such that if it is expressed in excess, cancerous growth can result.

Ca2+ signaling is believed to play an important role in the regulation of cell growth and differentiation [20] as well as in apoptosis [19] (discussed below). Ca2+ generally is required in the incubation medium for activation of mitogenesis, and in many instances, documented increases in [Ca2+]i are associated with the actions of mitogenic agents. Calcium ionophores or thapsigargin can stimulate DNA synthesis, especially if combined with a PKC activator such as an active phorbol ester. This action of phorbol esters may explain their well-known tumor-promoting activity, but this has not been proven.

In addition to cytoplasmic Ca2+ serving as a regulator of mitogenesis, there is evidence for a role of intracellular Ca2+ stores, perhaps implicating a role for capacitative calcium ion entry. Interestingly, in various cell lines, depletion of intracellular stores by thapsigargin has been shown to induce mitogenesis; a quiescent, or Go, state; or apoptosis. These differential effects could result from thapsigargin-induced Ca2+ signals or from inhibition of protein synthesis due to the diminished concentrations of stored Ca2+. The concentration of ER Ca2+ plays an important role at various steps involved in protein synthesis. In those instances in which prolonged treatment with thapsigargin induces apoptosis, inhibition of protein synthesis could contribute to this process as well.

Sustained increases in intracellular Ca2+ have toxic effects on cells [21]. However, in the case of thapsigargin, it appears that the cells are killed by the specific, genetically programmed process known as apoptosis. When cells die due to toxic insult, the process is often one of necrosis; this is a relatively nonspecific process involving cell lysis, the release of cellular contents, which subsequently must be “cleaned up” by the immune system, involving an inflammatory reaction. However, complex organisms also have the need for cells to die at appropriate times in development and in maintenance of normal organ function. In such instances, a more orderly, noninflammatory process of programmed cell death, or apoptosis, occurs. This involves degradation of nuclear DNA by specific endonucleases, resulting in the characteristic DNA ladders which are diagnostic of apoptosis; cellular shrinkage; and ultimately the packaging of cellular constituents in membrane-delimited structures, known as apoptotic bodies, for disposition by leukocytes [19].

There is considerable evidence for a role of Ca2+ signaling in apoptosis [19]. For example, studies of glucocorticoid-induced apoptosis have identified a Ca2+ influx associated with lymphoid cell death. In addition, the action of glucocorticoids to induce apoptosis could be mimicked by Ca2+ ionophores. Similarly, thapsigargin triggers a full apoptotic response. Chelation of Ca2+ by intracellular chelators, extracellular EGTA, or overexpression of the Ca2+-binding protein calbindin inhibits apoptosis due to glucocorticoids and other agents. Finally, calmodulin antagonists have been reported to disrupt apoptosis in a variety of systems. Together these data suggest a central role for Ca2+ in apoptosis in response to glucocorticoids and other agents [19]. However, there is also evidence that in addition to changes in cytoplasmic calcium serving as a signal or modulator for apoptosis, a fall in the concentration of Ca2+ in the ER can signal a full apoptotic response, independently of the associated rise in cytoplasmic Ca2+ [22]. It is not clear at this time whether this involves the same signaling pathway involved in capacitative calcium ion entry.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28115

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