ArticleHuman molecular genetics2020
Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise.The Journal of physiology · 2026Article
- Establishment and evaluation of a prognostic model for sodium overload necrosis in acute myeloid leukemia.Translational cancer research · 2026Article
- A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults.PloS one · 2026Article
- Feedback modulation of Orai1α and Orai1β protein content mediated by STIM proteins.Journal of cellular physiology · 2025Article
- Article
- Methods to Quantify the Dynamic Recycling of Plasma Membrane Channels.Bio-protocol · 2023Article
- Nuanced Interactions between AKAP79 and STIM1 with Orai1 CaMolecular and cellular biology · 2022Article
- Distinct roles of ORAI1 in T cell-mediated allergic airway inflammation and immunity to influenza A virus infection.Science advances · 2022Article
- Store-operated calcium channels in skin.Frontiers in physiology · 2022Review
- Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.Molecular cell · 2021Article
- TRPM4 in Cancer-A New Potential Drug Target.Biomolecules · 2021Review
- More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins.International journal of molecular sciences · 2021Review
- AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 CaFunction (Oxford, England) · 2021Article
- Orai channels: key players in CaCurrent opinion in physiology · 2020Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Loss-of function mutations in Orai1 Ca2+ channels lead to a form of severe combined immunodeficiency, auto-immunity, muscle hypotonia and defects in dental enamel production and sweat gland function. Two single-nucleotide polymorphisms (SNPs) in Orai1 have been found and localize to the second extracellular loop. These polymorphisms associate with atopic dermatitis but how they affect Ca2+ signalling and cell function is unknown. Here, we find that Orai1-SNPs turnover considerably more slowly than wild type Orai1 and are more abundantly expressed in the plasma membrane. We show a central role for flotillin in the endocytotic recycling of Orai1 channels and that endocytosed wild type Orai1 is trafficked to Rab 7-positive late endosomes for lysosomal degradation. Orai1-SNPs escape the degradation pathway and instead enter Rab 11-positive recycling endosomes, where they are returned to the surface membrane through Arf6-dependent exocytosis. We find that Orai1-SNPs escape late endosomes through endosomal pH regulation of interaction between the channel and flotillin. We identify a pH-sensitive electrostatic interaction between positively charged arginine in extracellular loop 2 (K210) and a negatively charged aspartate (D112) in extracellular loop 1 that helps determine Orai1 turnover. The increase in membrane Orai1-SNP leads to a mis-match in Orai1-STIM stoichiometry, resulting in inhibition of Ca2+ entry and Ca2+-dependent gene expression. Our results identify new strategies for targeting atopic dermatitis.
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