Key Points
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A rise in cytoplasmic Ca2+ concentration acts as a universal intracellular messenger that drives numerous cellular responses.
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In many cell types, a major route for Ca2+ influx is through store-operated Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane. These ion channels are activated by the process of emptying the intracellular Ca2+ stores.
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The molecular basis of this ubiquitous Ca2+ entry mechanism has recently been unravelled with the discoveries of stromal interaction molecule 1 (STIM1), a protein that senses the Ca2+ content of the stores, and ORAI1 (also known as CRACM1), which forms the CRAC channel pore.
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Ca2+ entry through CRAC channels activates various temporally distinct responses, ranging from exocytosis to cell growth and proliferation.
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Aberrant CRAC channel activity has been linked to several debilitating human diseases, including certain types of immunodeficiency and autoimmunity disorders, allergy, and inflammatory bowel disease.
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Although in its early stages, drugs targeting the CRAC channel pathway are now being developed and should prove useful in treating a range of immune and non-immune disorders.
Abstract
Elevation of cytosolic Ca2+ levels through the activation of store-operated Ca2+ release-activated Ca2+ (CRAC) channels is involved in mediating a disparate array of cellular responses. These include secretion, metabolism and gene expression, as well as cell growth and proliferation. Moreover, emerging evidence points to the involvement of aberrant CRAC channel activity in human diseases, such as certain types of immunodeficiency and autoimmunity disorders, allergy, and inflammatory bowel disease. This article summarizes recent advances in understanding the gating and function of CRAC channels, their links to human disease and key issues for the development of channel blockers.
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Acknowledgements
Work in my laboratory is supported by the Medical Research Council and the British Heart Foundation. I thank D. Bakowski for comments on the manuscript.
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Glossary
- SERCA
-
Sarco/endoplasmic reticulum Ca2+ ATPase pump, which transports Ca2+ from the cytosol into the endoplasmic reticulum.
- Fluctuation analysis
-
A method that extracts information concerning the nature of individual channel events from statistical descriptions of the current noise.
- Transient receptor potential (TRP) ion channel family
-
A broad family of largely non-selective cation channels permeable to Na+ and Ca2+. TRP channels were first discovered in the trp mutant strain of Drosophila melanogaster.
- EF-hand domain
-
A highly conserved Ca2+ binding site found in many Ca2+-binding proteins.
- Sterile α-motif domain
-
A putative protein–protein interaction module that helps drive homo-oligomerization and hetero-oligomerization.
- Ezrin-radixin-moesin
-
A group of actin-binding proteins that link actin with plasma membrane proteins and are involved in signal transduction.
- ICRAC
-
The current that flows through Ca2+ release-activated Ca2+ (CRAC) channels.
- Muscular hypotonia
-
Decreased muscle tone.
- Ectodermal dysplasia
-
Abnormalities of ectodermal structures including hair, nails, sweat glands and teeth. These abnormalities can lead to reduced sweat production and reduced dental enamel formation.
- Puncta
-
Hot-spots or clusters of stromal interaction molecule 1 (STIM1) at endoplasmic reticulum–plasma membrane regions just below the plasma membrane.
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Parekh, A. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 9, 399–410 (2010). https://doi.org/10.1038/nrd3136
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DOI: https://doi.org/10.1038/nrd3136
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