ISSN: 2157-7013
Journal of Cell Science & Therapy
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Genetic Variants of Store-Operated Channels and Human Diseases

Wei-Chiao Chang*
Department of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
Corresponding Author : Wei-Chiao Chang
Department of Medical Genetics
Kaohsiung Medical University
Kaohsiung, Taiwan; Cancer Center
Kaohsiung Medical University Hospital
Kaohsiung; School of Pharmacy, College of Pharmacy
Taipei Medical University, Taipei, Taiwan
E-mail: wcc@kmu.edu.tw
Received May 15, 2012; Accepted May 18, 2012; Published May 21, 2012
Citation: Chang WC (2012) Genetic Variants of Store-Operated Channels and Human Diseases. J Cell Sci Ther 3:e108. doi: 10.4172/2157-7013.1000e108
Copyright: © 2012 Chang WC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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The functional role of Ca2+ influx in non-excitable cells was elusive for many years. In 1986, Prof. Putney [1] 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 [2] 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. [5] 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. [6], 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 [9], ORAI1/CRACM1 in mast cell degranulation [10] and cancer cell development [11,12].
The first study of a genetic defection ORAI1 in humans was reported by Feske et al. [5], 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 [13]. 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 [14]. 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 [15]. 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 [16]. 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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