[Frontiers in Bioscience E4, 2253-2268, January 1, 2012]

Physiological and pathophysiological functions of SOCE in the immune system

Patrick J. Shaw1, Stefan Feske1

1Department of Pathology, New York University Langone Medical Center, New York, NY 10016

TABLE OF CONTENTS

1. Abstract
2. Introduction to store-operated calcium entry (SOCE) by STIM and ORAI proteins
3. The role of STM1 and ORAI1 in immune cell functions
3.1. Effector CD4+ T cells
3.2. Regulatory T cells
3.3. Cytotoxic lymphocytes
3.4. B cells
3.5. Dendritic cells
3.6. Mast cells
3.7. Macrophages
3.8. Neutrophils
4. Immune Deficiencies associated with defects in SOCE
4.1. Mutations in immunoreceptor-associated genes upstream of store-depletion
4.2. Mutations in CRAC channel genes ORAI1 and STIM1
4.2.1. Mutations in ORAI1
4.2.2. Mutations in STIM1
4.3. Clinical manifestations of ORAI1 and STIM1 deficiency
4.3.1. Immunodeficiency and autoimmunity
4.3.2. Non-immunological symptoms of SOCE deficiency
5. Conclusions
6. Acknowledgements
7. References

1. ABSTRACT

Calcium signals play a critical role in many cell-type specific effector functions during innate and adaptive immune responses. The predominant mechanism to raise intracellular (Ca2+) used by most immune cells is store-operated Ca2+ entry (SOCE), whereby the depletion of endoplasmic reticulum (ER) Ca2+ stores triggers the influx of extracellular Ca2+. SOCE in immune cells is mediated by the highly Ca2+ selective Ca2+-release-activated Ca2+ (CRAC) channel, encoded by ORAI1, ORAI2 and ORAI3 genes. ORAI proteins are activated by stromal interaction molecules (STIM) 1 and 2, which act as sensors of ER Ca2+ store depletion. The importance of SOCE mediated by STIM and ORAI proteins for immune function is evident from the immunodeficiency and autoimmunity in patients with mutations in STIM1 and ORAI1 genes. These patients and studies in gene-targeted mice have revealed an essential role for ORAI/STIM proteins in the function of several immune cells. This review focuses on recent advances made towards understanding the role of SOCE in immune cells with an emphasis on the immune dysregulation that results from defects in SOCE in human patients and transgenic mice.