Cochlear marginal cells and vestibular dark cells transport potassium into the inner ear endolymph, a potassium-rich fluid, the homeostasis of which is essential for hearing and balance. We have formulated an integrated mathematical model of ion transport across these epithelia that incorporates the biophysical properties of the major ion transporters and channels located in the apical and basolateral membranes of the constituent cells. The model is constructed for both open- and short-circuit situations to test the extremes of functional capacity of the epithelium and predicts the steady-state voltages, ion concentrations, and transepithelial currents as a function of various transporter and channel densities. We validate the model by establishing that the cells are capable of vectorial ion transport consistent with several experimental measurements. The model indicates that cochlear marginal cells do not make a significant direct contribution to the endocochlear potential and illustrates how changes to the activity of specific transport proteins lead to reduced K(+) flux across the marginal and dark cell layers. In particular, we investigate the mechanisms of loop diuretic ototoxicity and diseases with hearing loss in which K(+) and Cl(-) transport are compromised, such as Jervell and Lange-Nielsen syndrome and Bartter syndrome, type IV, respectively. Such simulations demonstrate the utility of compartmental modeling in investigating the role of ion homeostasis in inner ear physiology and pathology.

译文

耳蜗边缘细胞和前庭暗细胞将钾输送到内耳内淋巴中,内淋巴是一种富含钾的液体,其稳态对于听力和平衡至关重要。我们已经建立了跨这些上皮细胞的离子转运的综合数学模型,该模型结合了位于组成细胞的顶膜和基底外侧膜中的主要离子转运蛋白和通道的生物物理特性。该模型是针对开路和短路情况构建的,以测试上皮功能能力的极限,并预测稳态电压,离子浓度和跨上皮电流与各种转运蛋白和通道密度的关系。我们通过建立细胞能够与几种实验测量一致的矢量离子传输来验证模型。该模型表明,耳蜗边缘细胞对耳蜗内电位没有明显的直接贡献,并说明了特定转运蛋白活性的变化如何导致边缘细胞层和暗细胞层的K () 通量减少。特别是,我们研究了环利尿剂耳毒性的机制以及K () 和Cl(-) 转运受损的听力损失疾病,例如Jervell和Lange-Nielsen综合征以及IV型Bartter综合征。此类模拟证明了隔室建模在研究离子稳态在内耳生理和病理学中的作用方面的实用性。

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