ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain

Gain‐of‐function mutations in the highly selective Ca2+ channel ORAI1 cause tubular aggregate myopathy (TAM) characterized by muscular pain, weakness and cramping. TAM‐associated mutations in ORAI1 first and third transmembrane domain facilitate channel opening by STIM1, causing constitutive Ca2+ influx and increasing the currents evoked by Ca2+ store depletion. Mutation V107M additionally decreases the channel selectivity for Ca2+ ions and its inhibition by acidic pH, while mutation T184M does not alter the channel sensitivity to pH or to reactive oxygen species. The ORAI blocker GSK‐7975A prevents the constitutive activity of TAM‐associated channels and might be used in therapy for patients suffering from TAM.

• Publication year

  2018

• Venue

  Journal of Physiology

• Publication date

  2018-11-28

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1113/JP277079PMID 30382595PMCID 6332830
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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