Kozel P J, Friedman R A, Erway L C, Yamoah E N, Liu L H, Riddle T, Duffy J J, Doetschman T, Miller M L, Cardell E L, Shull G E
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
J Biol Chem. 1998 Jul 24;273(30):18693-6. doi: 10.1074/jbc.273.30.18693.
Plasma membrane Ca2+-ATPase isoform 2 (PMCA2) exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiological functions than some of the other isoforms. A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice. Breeding of heterozygous mice yielded live homozygous mutant offspring. PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance. Histological analysis of the cerebellum and inner ear of mutant and wild-type mice revealed that null mutants had slightly increased numbers of Purkinje neurons (in which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory evoked brainstem responses revealed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrate that PMCA2 is required for both balance and hearing and suggest that it may be a major source of the calcium used in the formation and maintenance of otoconia.
质膜钙ATP酶同工型2(PMCA2)表现出高度受限的组织分布,这表明它比其他一些同工型具有更特殊的生理功能。耳蜗外毛细胞和螺旋神经节细胞中PMCA2的高表达表明其在听力方面具有独特作用。为了分析PMCA2的生理作用,我们利用基因打靶技术培育出了PMCA2基因缺失的小鼠。杂合小鼠繁殖产生了存活的纯合突变后代。PMCA2基因缺失的小鼠比杂合和野生型小鼠生长得更慢,表现出步态不稳和维持平衡困难。对突变型和野生型小鼠的小脑和内耳进行组织学分析发现,纯合突变体中浦肯野神经元数量略有增加(PMCA2在其中高度表达),分子层厚度减小,前庭系统中没有耳石,以及柯蒂氏器存在一系列异常。对听觉诱发脑干反应的分析表明,纯合突变体耳聋,杂合小鼠有明显的听力损失。这些数据表明PMCA2对平衡和听力都是必需的,并表明它可能是耳石形成和维持过程中所用钙的主要来源。