Tauris Jacob, Christensen Erik Ilsø, Nykjaer Anders, Jacobsen Christian, Petersen Claus Munck, Ovesen Therese
Department of Otorhinolaryngology, Aarhus University Hospital, Aarhus, Denmark.
Audiol Neurootol. 2009;14(4):267-78. doi: 10.1159/000199446. Epub 2009 Feb 6.
Cubilin and megalin are multifunctional endocytotic receptors expressed in many absorptive epithelia. The receptors have separate functions but may act in concert in several tissues including the small intestine, the visceral yolk sac and the renal proximal tubule to perform significant physiological functions essential to homeostasis in the extracellular fluid compartments. Because of the importance of fluid homeostasis in the inner ear, we investigated the expression of cubilin and megalin in this structure. Furthermore, we examined the binding properties of 6 different aminoglycosides (AGs) to cubilin and compared the results to data obtained for megalin, which is a well-known receptor for AGs and other polybasic substances, including several ototoxic drugs. In the cochlea, immunohistochemical labelling for cubilin showed expression corresponding to the apical surface of the strial marginal cells, to epithelial cells at the spiral prominence and to epithelial cells of Reissner's membrane facing the cochlear duct. In the vestibular apparatus, positive labelling was found in dark cells of the utricle and those flanking the crista ampullaris of the semicircular canals. Exactly the same tissue distribution was found for megalin. These findings support the prevailing view that cubilin and megalin constitute a dual-receptor complex facilitating the function of each other. The physiological role of this receptor complex in the inner ear remains unknown, although several established ligands for both cubilin and megalin are present in the inner ear fluids. Receptor-ligand interaction analysis showed that all 6 AGs bind to both receptors and with approximately the same affinity. The results demonstrate a novel role for cubilin as a drug receptor for AGs and possibly other ototoxic substances.
立方转铁蛋白和巨转铁蛋白是在许多吸收性上皮中表达的多功能内吞受体。这两种受体具有各自独立的功能，但在包括小肠、内脏卵黄囊和近端肾小管在内的多个组织中可能协同发挥作用，以执行细胞外液隔室中对体内平衡至关重要的重要生理功能。由于内耳中液体平衡的重要性，我们研究了立方转铁蛋白和巨转铁蛋白在该结构中的表达。此外，我们检测了6种不同氨基糖苷类药物（AGs）与立方转铁蛋白的结合特性，并将结果与巨转铁蛋白的数据进行比较，巨转铁蛋白是AGs和其他多碱性物质（包括几种耳毒性药物）的著名受体。在耳蜗中，立方转铁蛋白的免疫组化标记显示其表达对应于血管纹边缘细胞的顶端表面、螺旋隆起处的上皮细胞以及面对蜗管的Reissner膜的上皮细胞。在前庭器官中，在椭圆囊的暗细胞和半规管壶腹嵴两侧的细胞中发现了阳性标记。巨转铁蛋白的组织分布完全相同。这些发现支持了普遍的观点，即立方转铁蛋白和巨转铁蛋白构成了一个相互促进功能的双受体复合物。尽管内耳液中存在几种已确定的立方转铁蛋白和巨转铁蛋白的配体，但该受体复合物在内耳中的生理作用仍然未知。受体 - 配体相互作用分析表明，所有6种AGs均与这两种受体结合，且亲和力大致相同。结果表明立方转铁蛋白作为AGs以及可能其他耳毒性物质的药物受体具有新的作用。
