Research ArticleCalcium signaling

Differential regulation of Ca2+ influx by ORAI channels mediates enamel mineralization

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Science Signaling  23 Apr 2019:
Vol. 12, Issue 578, eaav4663
DOI: 10.1126/scisignal.aav4663

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Preventing CRAC’d teeth

Store-operated Ca2+ entry (SOCE) through CRAC channels, specifically complexes formed by ORAI Ca2+ channels and STIM Ca2+ sensors, mediates Ca2+ uptake in enamel cells in teeth. Eckstein et al. described a patient with a null mutation in ORAI1 that likely accounted for the defective enamel mineralization in his teeth. In mice, deficiency of ORAI1, but not that of ORAI2, decreased SOCE in enamel cells and resulted in compromised enamel structure. In an enamel cell line, ORAI1 knockdown increased mitochondrial cellular respiration, resulting in altered redox status that increased the efficiency of Ca2+ uptake in the ER. These results indicate that ORAI1 is the major CRAC channel in enamel cells and reveal the mechanisms by which SOCE affects enamel cell function.

Abstract

Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular functions. Mutations in the human ORAI1 gene result in immunodeficiency, anhidrotic ectodermal dysplasia, and enamel defects. In our investigation of the role of ORAI proteins in enamel, we identified enamel defects in a patient with an ORAI1 null mutation. Targeted deletion of the Orai1 gene in mice showed enamel defects and reduced SOCE in isolated enamel cells. However, Orai2−/− mice showed normal enamel despite having increased SOCE in the enamel cells. Knockdown experiments in the enamel cell line LS8 suggested that ORAI2 and ORAI3 modulated ORAI1 function, with ORAI1 and ORAI2 being the main contributors to SOCE. ORAI1-deficient LS8 cells showed altered mitochondrial respiration with increased oxygen consumption rate and ATP, which was associated with altered redox status and enhanced ER Ca2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of ORAI1 in Ca2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.

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