ArticleThe Journal of general physiology2007
Orai1 mutations alter ion permeation and Ca2+-dependent fast inactivation of CRAC channels: evidence for coupling of permeation and gating.
Article in The Journal of general physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- STIM-Orai signaling in neurons: integrating calcium dynamics and synaptic plasticity.Cell communication and signaling : CCS · 2026Review
- Is the SPLUNC1-Orai1 axis a critical determinant of lung health?Biochemical Society transactions · 2025Review
- Store-Operated Calcium Channels in the Nervous System.Annual review of physiology · 2025Review
- Water in peripheral TM-interfaces of Orai1-channels triggers pore opening.Communications biology · 2024Article
- A pathogenic human Orai1 mutation unmasks STIM1-independent rapid inactivation of Orai1 channels.eLife · 2023Article
- Regulatory mechanisms controlling store-operated calcium entry.Frontiers in physiology · 2023Review
- STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases.Frontiers in aging · 2022Review
- Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond.Cells · 2021Review
- The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local CaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- The Orai Pore Opening Mechanism.International journal of molecular sciences · 2021Review
- Store-Operated Calcium Entry in the Cardiovascular System.Advances in experimental medicine and biology · 2021Review
- Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer.Frontiers in pharmacology · 2021Review
- Interrogating permeation and gating of Orai channels using chemical modification of cysteine residues.Methods in enzymology · 2021Article
- Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.Frontiers in cell and developmental biology · 2021Article
- Molecular Choreography and Structure of CaMembranes · 2020Review
- Molecular basis of allosteric Orai1 channel activation by STIM1.The Journal of physiology · 2020Review
- The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases.Frontiers in immunology · 2020Review
- Critical parameters maintaining authentic CRAC channel hallmarks.European biophysics journal : EBJ · 2019Review
- Toward a Model for Activation of Orai Channel.iScience · 2019Article
25 more citing papers are in PubMed but not listed here.
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4 authors.
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Abstract
Ca(2+) entry through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels is an essential trigger for lymphocyte activation and proliferation. The recent identification of Orai1 as a key CRAC channel pore subunit paves the way for understanding the molecular basis of Ca(2+) selectivity, ion permeation, and regulation of CRAC channels. Previous Orai1 mutagenesis studies have indicated that a set of conserved acidic amino acids in trans membrane domains I and III and in the I-II loop (E106, E190, D110, D112, D114) are essential for the CRAC channel's high Ca(2+) selectivity. To further dissect the contribution of Orai1 domains important for ion permeation and channel gating, we examined the role of these conserved acidic residues on pore geometry, properties of Ca(2+) block, and channel regulation by Ca(2+). We find that alteration of the acidic residues lowers Ca(2+) selectivity and results in striking increases in Cs(+) permeation. This is likely the result of enlargement of the unusually narrow pore of the CRAC channel, thus relieving steric hindrance for Cs(+) permeation. Ca(2+) binding to the selectivity filter appears to be primarily affected by changes in the apparent on-rate, consistent with a rate-limiting barrier for Ca(2+) binding. Unexpectedly, the mutations diminish Ca(2+)-mediated fast inactivation, a key mode of CRAC channel regulation. The decrease in fast inactivation in the mutant channels correlates with the decrease in Ca(2+) selectivity, increase in Cs(+) permeability, and enlargement of the pore. We propose that the structural elements involved in ion permeation overlap with those involved in the gating of CRAC channels.
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