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The versatility and universality of calcium signalling

Nature Reviews Molecular Cell Biology volume 1, pages 1121 (2000) | Download Citation

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Abstract

The universality of calcium as an intracellular messenger depends on its enormous versatility. Cells have a calcium signalling toolkit with many components that can be mixed and matched to create a wide range of spatial and temporal signals. This versatility is exploited to control processes as diverse as fertilization, proliferation, development, learning and memory, contraction and secretion, and must be accomplished within the context of calcium being highly toxic. Exceeding its normal spatial and temporal boundaries can result in cell death through both necrosis and apoptosis.

Key points

  • Versatility in Ca2+ signalling is provided by a toolkit that can be divided into four types of tool:

    • Ca2+-mobilizing signals include the four intracellular messengers inositol-1,4,5-trisphosphate, cyclic ADP ribose, nicotinic acid dinucleotide phosphate and sphingosine-1-phosphate. Membrane depolarization increases Ca2+ in excitable cells.

    • ON mechanisms largely depend on channels in the plasma membrane or the endoplasmic/sarcoplasmic reticulum membrane. In both cases the result is an increase in the cytoplasmic Ca2+ concentration.

    • Ca2+ sensors, including the ubiquitous Ca2+-binding protein calmodulin and a wide variety of Ca2+?calmodulin-activated proteins, translate the ON mechanisms into physiological responses.

    • OFF mechanisms reduce the free cytoplasmic Ca2+ concentration by either sequestering it (Ca2+ buffers) or pumping it out of the cytoplasm.

  • Ca2+ can be mobilized as different types of elementary events: blips and quarks are caused by the opening of a single inositol-1,4,5-trisphosphate receptor or ryanodine receptor; puffs and sparks represent the opening of a group of such receptors. These can be built up into more complex intra- and intercellular Ca2+ signals such as waves.

  • The frequency of Ca2+ waves can vary among different cell types, and according to the intensity of the Ca2+-mobilizing signal.

  • Ca2+ signalling is used throughout the life cycle of an organism.

  • Processes that depend on Ca2+ signals include fertilization, axis formation, cell differentiation, proliferation, transcriptional activation and apoptosis.

  • An important challenge for the future will be understanding how individual cell types select their own unique Ca2+ signalling toolkit.

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Affiliations

  1. The Babraham Institute, Laboratory of Molecular Signalling, Babraham Hall, Babraham, Cambridge, CB2 4AT , UK.

    • Michael J. Berridge
    • , Peter Lipp
    •  & Martin D. Bootman
  2. Correspondence to M.J.B. michael.berridge@bbsrc.ac.uk

    • Michael J. Berridge

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Supplementary information

Glossary

Ca2+-INDUCED Ca2+ RELEASE

An autocatalytic mechanism by which cytoplasmic Ca2+ activates the release of Ca2+ from internal stores through channels such as inositol-1,4,5-trisphosphate receptors or ryanodine receptors.

VOLTAGE-OPERATED CHANNELS

Plasma-membrane ion channels that are activated by membrane depolarization.

RECEPTOR-OPERATED CHANNELS

Plasma membrane ion channels that open in response to binding of an extracellular ligand.

STORE-OPERATED CHANNELS

Plasma membrane ion channels, of uncertain identity, that open in response to depletion of internal Ca2+ stores.

CDC25

A dual-specificity threonine/tyrosine phosphatase required for progression of the cell cycle. It dephosphorylates and activates cyclin?CDK complexes.

SOMITES

A series of paired blocks of cells that form during early vertebrate development and give rise to the backbone and body muscle.

SPHINGOMYELIN SIGNALLING

Several metabolites of sphingomyelin affect apoptosis through poorly undertood mechanisms: ceramide and sphingomyelin are generally proapoptotic whereas sphingosine 1-phosphate is generally antiapoptotic.

STRESS-ACTIVATED PROTEIN KINASES

Members of the mitogen-activated protein kinase (MAPK) family that are activated by stress, including c-Jun N-terminal kinase (JNK) and p38 MAPK.

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