Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (8), p.2895-2900
• Main Authors: Liao, Yanhong, Erxleben, Christian, Abramowitz, Joel, Flockerzi, Veit, Zhu, Michael Xi, Armstrong, David L, Birnbaumer, Lutz
• Format: Article
• Language: English
• Subjects: Bacterial Proteins; Biochemistry; Biological Sciences; Calcium; Calcium - metabolism; Calcium Channels - metabolism; Cell Line; Cell lines; Cell membranes; Electric current; Electrophysiology; Eukaryotes; Gene Expression Regulation; HEK293 cells; Humans; Ion channels; Ion Transport - physiology; Luminescent Proteins; Membrane Proteins - metabolism; Models, Biological; Molecules; Neoplasm Proteins - metabolism; ORAI1 Protein; Plasmids; Receptors; Signal transduction; Stromal Interaction Molecule 1; Transfection; TRPC Cation Channels - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712288105

Receptor-operated Ca²⁺ entry (ROCE) and store-operated Ca²⁺ entry (SOCE) into cells are functions performed by all higher eukaryotic cells, and their impairment is life-threatening. The main molecular components of this pathway appear to be known. However, the molecular make-up of channels mediating ROCE and SOCE is largely unknown. One hypothesis proposes SOCE channels to be formed solely by Orai proteins. Another proposes SOCE channels to be composed of both Orai and C-type transient receptor potential (TRPC) proteins. Both hypotheses propose that the channels are activated by STIM1, a sensor of the filling state of the Ca²⁺ stores that activates Ca²⁺ entry when stores are depleted. The role of Orai in SOCE has been proven. Here we show the TRPC-dependent reconstitution of Icrac, the electrophysiological correlate to SOCE, by expression of Orai1; we also show that R91W-Orai1 can inhibit SOCE and ROCE and that Orai1 and STIM1 expression leads to functional expression of Gd-resistant ROCE. Because channels that mediate ROCE are accepted to be formed with the participation of TRPCs, our data show functional interaction between ROCE and SOCE components. We propose that SOCE/Icrac channels are composed of heteromeric complexes that include TRPCs and Orai proteins.