Zwaal R R, Van Baelen K, Groenen J T, van Geel A, Rottiers V, Kaletta T, Dode L, Raeymaekers L, Wuytack F, Bogaert T
Devgen N.V., Technologiepark 9, B-9052 Zwijnaarde, Belgium.
J Biol Chem. 2001 Nov 23;276(47):43557-63. doi: 10.1074/jbc.M104693200. Epub 2001 Sep 14.
The sarco-endoplasmic reticulum Ca(2+)-transport ATPase (SERCA) loads intracellular releasable Ca(2+) stores by transporting cytosolic Ca(2+) into the endoplasmic (ER) or sarcoplasmic reticulum (SR). We characterized the only SERCA homologue of the nematode Caenorhabditis elegans, which is encoded by the sca-1 gene. The sca-1 transcript is alternatively spliced in a similar mode as the vertebrate SERCA2 transcript, giving rise to two protein variants: CeSERCAa and CeSERCAb. These proteins showed structural and functional conservation to the vertebrate SERCA2a/b proteins. The CeSERCAs were primarily expressed in contractile tissues. Loss of CeSERCA through gene ablation or RNA interference resulted in contractile dysfunctioning and in early larval or embryonic lethality, respectively. Similar defects could be induced pharmacologically using the SERCA-specific inhibitor thapsigargin, which bound CeSERCA at a conserved site. The conservation of SERCA2 homologues in C. elegans will allow genetic and chemical suppressor analyses to identify promising drug targets and lead molecules for treatment of SERCA-related diseases such as heart disease.
肌浆网内质网钙转运ATP酶（SERCA）通过将胞质Ca(2+)转运到内质网（ER）或肌浆网（SR）中来加载细胞内可释放的Ca(2+)储存库。我们对秀丽隐杆线虫唯一的SERCA同源物进行了表征，它由sca-1基因编码。sca-1转录本与脊椎动物SERCA2转录本以相似的方式进行可变剪接，产生两种蛋白质变体：CeSERCAa和CeSERCAb。这些蛋白质在结构和功能上与脊椎动物SERCA2a/b蛋白具有保守性。CeSERCAs主要在收缩组织中表达。通过基因敲除或RNA干扰缺失CeSERCA分别导致收缩功能障碍和早期幼虫或胚胎致死。使用SERCA特异性抑制剂毒胡萝卜素进行药理学处理可诱导类似缺陷，毒胡萝卜素在一个保守位点与CeSERCA结合。秀丽隐杆线虫中SERCA2同源物的保守性将使遗传和化学抑制剂分析能够识别有前景的药物靶点和先导分子，用于治疗SERCA相关疾病，如心脏病。
