Key Role for Store-Operated Ca2+ Channels in Activating Gene Expression in Human Airway Bronchial Epithelial Cells

Ca 2+ entry into airway epithelia is important for activation of the NFAT family of transcription factors and expression of genes including epidermal growth factor that help orchestrate local inflammatory responses. However, the identity of epithelial Ca 2+ channel that activates these transcriptional responses is unclear. In many other non-excitable cells, store-operated Ca 2+ entry is a major route for Ca 2+ influx and is mediated by STIM1 and Orai1 proteins. This study was performed to determine if store-operated Ca 2+ channels were expressed in human bronchial epithelial cells and, if so, whether they coupled Ca 2+ entry to gene expression. Cytoplasmic Ca 2+ measurements, patch clamp recordings, RNAi knockdown and functional assays were used to identify and then investigate the role of these Ca 2+ channels in activating the NFAT and c-fos pathways and EGF expression. STIM1 and Orai1 mRNA transcripts as well as proteins were robustly in epithelial cells and formed functional Ca 2+ channels. Ca 2+ entry through the channels activated expression of c-fos and EGF as well as an NFAT-dependent reporter gene. Store-operated Ca 2+ entry was also important for epithelial cell migration in a scrape wound assay. These findings indicate that store-operated Ca 2+ channels play an important role in stimulating airway epithelial cell gene expression and therefore comprise a novel potential therapeutic target for the treatment of chronic asthma and related airway disorders.