Davis Felicity M, Goulding Eugenia H, D'Agostin Diane M, Janardhan Kyathanahalli S, Cummings Connie A, Bird Gary S, Eddy Edward M, Putney James W
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Cell Calcium. 2016 Apr;59(4):189-97. doi: 10.1016/j.ceca.2016.02.007. Epub 2016 Feb 27.
Store-operated calcium entry (SOCE) is an important Ca(2+) influx pathway in somatic cells. In addition to maintaining endoplasmic reticulum (ER) Ca(2+) stores, Ca(2+) entry through store-operated channels regulates essential signaling pathways in numerous cell types. Patients with mutations in the store-operated channel subunit ORAI1 exhibit defects in store-operated Ca(2+) influx, along with severe immunodeficiency, congenital myopathy and ectodermal dysplasia. However, little is known about the functional role of ORAI1 in germ cells and reproductive function in mice, or in men, since men with loss-of-function or null mutations in ORAI1 rarely survive to reproductive age. In this study, we investigated the role of ORAI1 in male reproductive function. We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development. These studies establish an essential in vivo role for store-operated ORAI1 channels in male reproductive function and identify these channels as potential non-steroidal regulators of male fertility.
储存性钙内流（SOCE）是体细胞中一种重要的Ca(2+)内流途径。除了维持内质网（ER）的Ca(2+)储存外，通过储存性通道的Ca(2+)内流还调节多种细胞类型中的重要信号通路。储存性通道亚基ORAI1发生突变的患者表现出储存性Ca(2+)内流缺陷，同时伴有严重免疫缺陷、先天性肌病和外胚层发育不良。然而，由于携带ORAI1功能丧失或无效突变的男性很少能存活至生育年龄，关于ORAI1在小鼠生殖细胞和生殖功能中的功能作用，以及在男性中的作用，我们知之甚少。在本研究中，我们调查了ORAI1在雄性生殖功能中的作用。我们发现Orai1(-/-)雄性小鼠不育，精子发生存在严重缺陷，在精子细胞伸长发育的中后期有明显不足。这些研究确立了储存性ORAI1通道在雄性生殖功能中的重要体内作用，并将这些通道确定为男性生育能力的潜在非甾体调节剂。
