Orai1 is an essential pore subunit of the CRAC channel

Murali Prakriya, Stefan Feske, Yousang Gwack, Sonal Srikanth, Anjana Rao*, Patrick G. Hogan

*Corresponding author for this work

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Abstract

Stimulation of immune cells causes depletion of Ca2+ from endoplasmic reticulum (ER) stores, thereby triggering sustained Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels, an essential signal for lymphocyte activation and proliferation. Recent evidence indicates that activation of CRAC current is initiated by STIM proteins, which sense ER Ca2+ levels through an EF-hand located in the ER lumen and relocalize upon store depletion into puncta closely associated with the plasma membrane. We and others recently identified Drosophila Orai and human Orai1 (also called TMEM142A) as critical components of store-operated Ca2+ entry downstream of STIM. Combined overexpression of Orai and Stim in Drosophila cells, or Orai1 and STIM1 in mammalian cells, leads to a marked increase in CRAC current. However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit. Here we show that Orai1 is a plasma membrane protein, and that CRAC channel function is sensitive to mutation of two conserved acidic residues in the transmembrane segments. E106D and E190Q substitutions in transmembrane helices 1 and 3, respectively, diminish Ca2+ influx, increase current carried by monovalent cations, and render the channel permeable to Cs+. These changes in ion selectivity provide strong evidence that Orai1 is a pore subunit of the CRAC channel.

Original languageEnglish (US)
Pages (from-to)230-233
Number of pages4
JournalNature
Volume443
Issue number7108
DOIs
StatePublished - Sep 14 2006

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    Prakriya, M., Feske, S., Gwack, Y., Srikanth, S., Rao, A., & Hogan, P. G. (2006). Orai1 is an essential pore subunit of the CRAC channel. Nature, 443(7108), 230-233. https://doi.org/10.1038/nature05122