Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants
Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants
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DOI：
10.1111/j.1749-6632.2003.tb07229.x
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Prasada, V
中科院分区：
文献类型：
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作者：
Shull, GE;Okunade, G;Prasada, V
已知质膜Ca 2+转运ATP酶（PMCAs）将Ca 2+从细胞中排出，肌质网Ca 2 +-ATP酶（SERCAs）和分泌途径Ca 2 +-ATP酶（SPCA）将Ca 2+螯合在细胞内细胞器中;然而，对单个异构体的具体生理功能了解较少。这一信息开始出现在对小鼠和人类携带相应基因无效突变的研究中。质膜Ca 2 +-ATP酶亚型2（PMCA 2）中具有靶向或自发突变的小鼠是深度耳聋的，并且由于内耳感觉毛细胞中PMCA 2的损失而具有平衡缺陷。在人类中，SERCA 1（ATP 2A 1）的突变导致Brody病，骨骼肌松弛受损; SERCA 2（ATP 2A 2）基因的一个拷贝的丢失导致Darier病，一种皮肤病; SPCA 1（ATP 20）基因的一个拷贝的丢失导致Hailey-Hailey病，另一种皮肤病。在小鼠中，SERCA 2无效突变体不能存活至出生，并且杂合SERCA 2突变体具有受损的心脏性能和鳞状细胞癌的高发病率。SERCA 3无效突变体存活并且看起来健康，但是血管平滑肌的内皮依赖性舒张受损并且胰腺β细胞中的Ca 2+信号传导改变。表型的多样性表明，不同的钙转运ATP酶亚型提供非常不同的生理功能。
It is known that plasma membrane Ca2+-transporting ATPases (PMCAs) extrude Ca2+ from the cell and that sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) and secretory pathway Ca2+-ATPases (SPCAs) sequester Ca2+ in intracellular organelles; however, the specific physiological functions of individual isoforms are less well understood. This information is beginning to emerge from studies of mice and humans carrying null mutations in the corresponding genes. Mice with targeted or spontaneous mutations in plasma membrane Ca2+-ATPase isoform 2 (PMCA2) are profoundly deaf and have a balance defect due to the loss of PMCA2 in sensory hair cells of the inner ear. In humans, mutations in SERCA1 (ATP2A1) cause Brody disease, an impairment of skeletal muscle relaxation; loss of one copy of the SERCA2 (ATP2A2) gene causes Darier disease, a skin disorder; and loss of one copy of the SPCA1 (ATP20) gene causes Hailey-Hailey disease, another skin disorder. In the mouse, SERCA2 null mutants do not survive to birth, and heterozygous SERCA2 mutants have impaired cardiac performance and a high incidence of squamous cell cancers. SERCA3 null mutants survive and appear healthy, but endothelium-dependent relaxation of vascular smooth muscle is impaired and Ca2+ signaling is altered in pancreatic beta cells. The diversity of phenotypes indicates that the various Ca2+-transporting ATPase isoforms serve very different physiological functions.