TY - JOUR
T1 - Differential regulation of Ca2+ influx by Orai channels mediates enamel mineralization
AU - Eckstein, Miriam
AU - Vaeth, Martin
AU - Aulestia, Francisco J.
AU - Costiniti, Veronica
AU - Kassam, Serena N.
AU - Bromage, Timothy G.
AU - Pedersen, Pal
AU - Issekutz, Thomas
AU - Idaghdour, Youssef
AU - Moursi, Amr M.
AU - Feske, Stefan
AU - Lacruz, Rodrigo S.
N1 - Funding Information:
This work was funded by the National Institute of Dental and Craniofacial Research (NIH/NIDCR) awards to R.S.L. (DE025639 and DE027679) and by NIH grants to S.F. (AI097302, AI130143, and AI107448).
Publisher Copyright:
© 2019 The Authors, some rights reserved;
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1126/scisignal.aav4663
DO - 10.1126/scisignal.aav4663
M3 - Article
C2 - 31015290
AN - SCOPUS:85065303210
SN - 1945-0877
VL - 12
JO - Science Signaling
JF - Science Signaling
IS - 578
M1 - aav4663
ER -