Knipper Marlies, Claussen Cathrin, Rüttiger Lukas, Zimmermann Ulrike, Lüllmann-Rauch Renate, Eskelinen Eeva-Liisa, Schröder Jenny, Schwake Michael, Saftig Paul
Biochemical Institute, Christian-Albrechts-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany.
J Physiol. 2006 Oct 1;576(Pt 1):73-86. doi: 10.1113/jphysiol.2006.116889. Epub 2006 Aug 10.
Our previous studies revealed a critical role of the lysosomal membrane protein LIMP2 in the regulation of membrane transport processes in the endocytic pathway. Here we show that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. In temporal overlap to hearing impairment, fluorescence immunohistochemical studies revealed that the potassium channel KCNQ1 and its beta-subunit KCNE1 were almost completely lost in the luminal part of marginal cells in the stria vascularis, affecting first higher and later also lower frequency processing cochlear turns. Concomitant with this, the expression of megalin, a multiligand endocytic receptor, was reduced in luminal surfaces of marginal cells within the stria vascularis. KCNQ1/KCNE1 and megalin were also lost in the dark cells of the vestibular system. Although LIMP2 is normally expressed in all cells of the stria vascularis, in the organ of Corti and cochlear neurons, the lack of LIMP2 preferentially caused a loss of KCNQ1/KCNE1 and megalin, and structural changes were only seen months later, indicating that these proteins are highly sensitive to disturbances in the lysosomal pathway. The spatio-temporal correlation of the loss of KCNQ1/KCNE1 surface expression and loss of hearing thresholds supports the notion that the decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss. Our findings suggest an important role for LIMP2 in the control of the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 and megalin in the stria vascularis.
我们之前的研究揭示了溶酶体膜蛋白LIMP2在调节内吞途径中的膜转运过程中起关键作用。在此我们表明，LIMP2基因缺陷型小鼠早在4周龄时就出现进行性高频听力损失和耳声发射减少。在与听力障碍的时间重叠中，荧光免疫组织化学研究显示，钾通道KCNQ1及其β亚基KCNE1在血管纹边缘细胞的管腔部分几乎完全缺失，首先影响高频，随后也影响低频处理的耳蜗螺旋。与此同时，多配体内吞受体巨膜蛋白在血管纹边缘细胞的管腔表面表达减少。KCNQ1/KCNE1和巨膜蛋白在前庭系统的暗细胞中也缺失。尽管LIMP2通常在血管纹的所有细胞、柯蒂氏器和耳蜗神经元中表达，但LIMP2的缺失优先导致KCNQ1/KCNE1和巨膜蛋白的缺失，而结构变化在数月后才出现，这表明这些蛋白质对溶酶体途径的干扰高度敏感。KCNQ1/KCNE1表面表达缺失与听力阈值丧失的时空相关性支持了功能性KCNQ1/KCNE1的下降可能是听力损失主要原因的观点。我们的研究结果表明，LIMP2在控制血管纹顶端表达的膜蛋白如KCNQ1、KCNE1和巨膜蛋白的定位和水平方面发挥重要作用。
