The Virginia Merrill Bloedel Hearing Research Center, Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195, USA.
Hear Res. 2013 Oct;304:41-8. doi: 10.1016/j.heares.2013.06.003. Epub 2013 Jun 18.
Tight regulation of calcium (Ca2+) concentrations in the stereocilia bundles of auditory hair cells of the inner ear is critical to normal auditory transduction. The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca2+ in the endolymph. This study characterizes a novel null Atp2b2 allele, dfw(i5), by examining cochlear anatomy, vestibular function and auditory physiology in mutant mice. Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca2+ inside the stereocilia bundles. However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene. This study further resolves the interaction between Atp2b2 and Cdh23 in a gene dosage and frequency-dependent manner, and finds that low frequencies are significantly affected by the interaction. In +/dfw(i5) mice, one mutant copy of Cdh23 is sufficient to cause broad frequency hearing impairment. Additionally, we report another modifying interaction with Atp2b2 on auditory sensitivity, possibly caused by an unidentified hearing loss gene in mice.
内耳毛细胞的静纤毛束中钙离子（Ca2+）浓度的严格调节对于正常听觉转导至关重要。质膜 Ca2+ATP 酶 2（PMCA2）由 Atp2b2 基因编码，是从听觉静纤毛清除 Ca2+的主要机制，使细胞内水平保持较低，也有助于维持内淋巴中足够的细胞外 Ca2+水平。本研究通过检查突变小鼠的耳蜗解剖结构、前庭功能和听觉生理学，对新型 Atp2b2 无效等位基因 dfw(i5)进行了特征描述。PMCA2 突变体中听觉功能的丧失可归因于静纤毛束内细胞内 Ca2+的失调。然而，围绕静纤毛的细胞外 Ca2+离子也需要刚性的钙粘蛋白 23，钙粘蛋白 23 是由 Cdh23 基因编码的静纤毛尖端连接的组成部分。本研究进一步以基因剂量和频率依赖的方式解决了 Atp2b2 和 Cdh23 之间的相互作用，并发现低频受到相互作用的显著影响。在+/dfw(i5) 小鼠中，一个突变的 Cdh23 拷贝足以引起广泛的频率听力损伤。此外，我们报告了另一个与 Atp2b2 的听觉敏感性修饰相互作用，可能是由小鼠中未识别的听力损失基因引起的。
