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CRAC channelopathies

  • Ion Channels, Receptors and Transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Store-operated Ca2+ entry (SOCE) is an important Ca2+ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca2+ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca2+]ER results in activation of plasma membrane Ca2+ channels that mediate sustained Ca2+ influx which is required for many cell functions as well as refilling of Ca2+ stores. The Ca2+ release activated Ca2+ (CRAC) channel is the best characterized SOC channel with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel, long mysterious, have been defined. ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER, and activates the CRAC channel upon store depletion by binding to ORAI1. Both proteins are widely expressed in many tissues in both human and mouse consistent with the widespread prevalence of SOCE and CRAC channel currents in many cells types. CRAC channelopathies in human patients with mutations in STIM1 and ORAI1 are characterized by abolished CRAC channel currents, lack of SOCE and—clinically—immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia. This article reviews the role of ORAI and STIM proteins for SOCE and CRAC channel function in a variety of cell types and tissues and compares the phenotypes of ORAI1 and STIM1-deficient human patients and mice with targeted deletion of Orai and Stim genes.

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Abbreviations

CRAC:

Calcium release activated calcium (channel)

EDA:

Anhydrotic ectodermal dysplasia

SCID:

Severe combined immunodeficiency

SERCA:

Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase

SOCE:

Store-operated calcium entry

STIM1:

Stromal interaction molecule 1

VSMC:

Vascular smooth muscle cells

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Acknowledgements

This work was supported by NIH grant AI066128 and a March of Dimes Foundation grant. I thank Dr. M. Prakriya for the critical reading of the manuscript and helpful suggestions.

Conflicts of interest

The author is a scientific co-founder and advisor of CalciMedica, a biotechnology company that seeks to develop CRAC channel inhibitors.

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  1. Department of Pathology, New York University, Langone Medical Center, SRB314, New York, NY, USA

    Stefan Feske

  2. Department of Pathology, New York University, Langone Medical Center, 550 First Avenue, New York, NY, 10016, USA

    Stefan Feske

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Feske, S. CRAC channelopathies. Pflugers Arch - Eur J Physiol 460, 417–435 (2010). https://doi.org/10.1007/s00424-009-0777-5

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