Differential regulation of Ca 2+ influx by Orai channels mediates enamel mineralization

Miriam Eckstein, Martin Vaeth, Francisco J. Aulestia, Veronica Costiniti, Serena N. Kassam, Timothy Bromage, Pal Pedersen, Thomas Issekutz, Youssef Idaghdhour, Amr Moursi, Stefan Feske, Rodrigo Lacruz

Research output: Contribution to journalArticle

Abstract

Store-operated Ca 2+ entry (SOCE) channels are highly selective Ca 2+ 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 Ca 2+ 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 Ca 2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of Orai1 in Ca 2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.

Original languageEnglish (US)
Article numberaav4663
JournalScience Signaling
Volume12
Issue number578
DOIs
StatePublished - Jan 1 2019

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Enamels
Dental Enamel
Endoplasmic Reticulum
Defects
Oxidation-Reduction
Genes
Ectodermal Dysplasia
Mutation
Gene Deletion
Cell membranes
Oxygen Consumption
Blood Proteins
Respiration
Membrane Proteins
Homeostasis
Adenosine Triphosphate
Cells
Cell Membrane
Pumps
Oxygen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Differential regulation of Ca 2+ influx by Orai channels mediates enamel mineralization . / Eckstein, Miriam; Vaeth, Martin; Aulestia, Francisco J.; Costiniti, Veronica; Kassam, Serena N.; Bromage, Timothy; Pedersen, Pal; Issekutz, Thomas; Idaghdhour, Youssef; Moursi, Amr; Feske, Stefan; Lacruz, Rodrigo.

In: Science Signaling, Vol. 12, No. 578, aav4663, 01.01.2019.

Research output: Contribution to journalArticle

Eckstein, M, Vaeth, M, Aulestia, FJ, Costiniti, V, Kassam, SN, Bromage, T, Pedersen, P, Issekutz, T, Idaghdhour, Y, Moursi, A, Feske, S & Lacruz, R 2019, ' Differential regulation of Ca 2+ influx by Orai channels mediates enamel mineralization ', Science Signaling, vol. 12, no. 578, aav4663. https://doi.org/10.1126/scisignal.aav4663
Eckstein, Miriam ; Vaeth, Martin ; Aulestia, Francisco J. ; Costiniti, Veronica ; Kassam, Serena N. ; Bromage, Timothy ; Pedersen, Pal ; Issekutz, Thomas ; Idaghdhour, Youssef ; Moursi, Amr ; Feske, Stefan ; Lacruz, Rodrigo. / Differential regulation of Ca 2+ influx by Orai channels mediates enamel mineralization In: Science Signaling. 2019 ; Vol. 12, No. 578.
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