|The functional role of Ca2+ influx in non-excitable cells was elusive for many years. In 1986, Prof. Putney  firstly proposed the concept of capacitative Ca2+ channels (also called store-operated channel). In his model, agonist-mediated empty of intracellular Ca2+ stores triggers the activation of calcium channels. In 1992, a series of patch clamp experiments by Hoth and Penner  identified a Ca2+-selective current that was evoked by intracellular stores. This calcium channel was named “Ca2+ release-activated Ca2+ (CRAC) channels”. However, there were two fundamental questions in the field. First, how is calcium ion detected within the calcium store? Second, what is the gene of store-operated calcium channel? By using siRNA screening, STIM1, an intracellular calcium sensor, was found in 2005 [3,4]. Furthermore, the molecular identification of store-operated calcium channel was emerged based on the studies from two laboratories. Feske et al.  identified ORAI1 as the key protein responsible for store-mediated Ca2+ influx. The loss of function mutation of ORAI1 causes human severe combined immune deficiency (SCID). Approaches of genome-wide RNAi screens in Drosophila cells, Vig et al. , identified CRACM1 (CRAC modulators 1) as a regulator in CRAC currents. Using in vitro cell-based studies, Parekh’s group provided evidence that Ca2+ entry through store-operated calcium channels triggered the generation of the pro-inflammatory signals-LTC4 [7,8]. Animal models revealed the significant roles of STIM1 , ORAI1/CRACM1 in mast cell degranulation  and cancer cell development [11,12].
|The first study of a genetic defection ORAI1 in humans was reported by Feske et al. , when a mutation (asparagine 91 to tryptophan) in exon 1 of the ORAI1 gene was detected in SCID patients. Due to the genetic mutation, lymphocytes failed to evoke store-operated calcium signals-mediated cytokines production. Feske’s group further identified three mutations (A103E, L194P and A88SfsX25) in ORAI1 gene that resulted in loss of channel functions . Recently, genetic polymorphisms in ORAI1 have been described. In genetic association studies (136 patients with nephrolithiasis and 500 controls), the C allele carrier of rs12313273 in ORAI1 gene was strongly associated to recurrent stone forming in calcium nephrolithiasis patients . Studies from patients with Ankylosing Spondylitis (AS) indicated a close correlation between haplotypes of ORAI1 (rs12313273 and rs7135617) and the risk of HLA-B27 positive AS . In addition, a large scale of human DNA screening (2,478 DNA samples from Taiwanese and Japanese populations) also suggests the involvement of ORAI1 polymorphisms in the susceptibility of atopic dermatitis . These genetics results, combined with the findings in animal studies as well as cellular studies, suggest ORAI1 might be an important target in immune/inflammatory responses.
|In conclusion, the field of store-operated channel has remarkably advanced in the past ten years. With high-throughput genomic screening, we can expect that more exciting findings will be revealed in the near future.
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