ArticleFrontiers in cell and developmental biology2021
Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.
Article in Frontiers in cell and developmental biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- Research progress on the role and mechanism of STIM and Orai protein-mediated store-operated calcium entry in cardiovascular diseases.Channels (Austin, Tex.) · 2026Review
- Evolutionarily conserved hydrophobicity and sterics in TM3/TM4 balance Orai1 pore opening.Protein science : a publication of the Protein Society · 2026Article
- Comprehensive Phenotypic and Genomic Study for Understanding the Variability in Susceptibility of Listeria monocytogenes to AMPs and Bacteriocins.Probiotics and antimicrobial proteins · 2026Article
- STIM-Orai signaling in neurons: integrating calcium dynamics and synaptic plasticity.Cell communication and signaling : CCS · 2026Review
- Water in peripheral TM-interfaces of Orai1-channels triggers pore opening.Communications biology · 2024Article
- Synthetic Biology Meets CaCells · 2024Review
- Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1.Nature communications · 2023Article
- ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets.Pharmaceuticals (Basel, Switzerland) · 2023Review
- CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development.Cancers · 2022Review
- The Role of Lipids in CRAC Channel Function.Biomolecules · 2022Review
- Orai1 Boosts SK3 Channel Activation.Cancers · 2021Article
- Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
STIM1-mediated activation of calcium selective Orai channels is fundamental for life. The three Orai channel isoforms, Orai1-3, together with their multiple ways of interplay, ensure their highly versatile role in a variety of cellular functions and tissues in both, health and disease. While all three isoforms are activated in a store-operated manner by STIM1, they differ in diverse biophysical and structural properties. In the present study, we provide profound evidence that non-conserved residues in TM3 control together with the cytosolic loop2 region the maintenance of the closed state and the configuration of an opening-permissive channel conformation of Orai1 and Orai3 in an isoform-specific manner. Indeed, analogous amino acid substitutions of these non-conserved residues led to distinct extents of gain- (GoF) or loss-of-function (LoF). Moreover, we showed that enhanced overall hydrophobicity along TM3 correlates with an increase in GoF mutant currents. Conclusively, while the overall activation mechanisms of Orai channels appear comparable, there are considerable variations in gating checkpoints crucial for pore opening. The elucidation of regions responsible for isoform-specific functional differences provides valuable targets for drug development selective for one of the three Orai homologs.
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