Computer modeling defines the system driving a constant current crucial for homeostasis in the mammalian cochlea by integrating unique ion transports

[Speaker] Fumiaki Nin:1
[Co-author] Takamasa Yoshida:2, Shingo Murakami:3, Genki Ogata:1, Satoru Uetsuka:4, Katsumi Doi:5, Seishiro Sawamura:1, Hidenori Inohara:4, Yoshihisa Kurachi:6, Hiroshi Hibino:1
1:Department of Molecular Physiology, Niigata University School of Medicine, Japan, 2:Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Japan, 3:Department of Physiology, School of Medicine, Toho University, Japan, 4:Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Japan, 5:Department of Otolaryngology, Faculty of Medicine, Kindai University, Japan, 6:Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan

The cochlear lateral wall an epithelial-like tissue comprising inner and outer layers maintains +80 mV in endolymph. This endocochlear potential (EP) supports hearing and represents the sum of all membrane potentials across apical and basolateral surfaces of both layers. Underlying extracellular and intracellular [K+] is likely controlled by the "circulation current," which crosses the two layers and unidirectionally flows throughout the cochlea. This idea was conceptually reinforced by our computational model integrating ion channels and transporters; however, contribution of the outer layer's basolateral surface remains unclear. Recent experiments showed that this basolateral surface transports K+ using Na+,K+-ATPases and an unusual characteristic of greater permeability to Na+ than to other ions. To determine whether and how these machineries are involved in the circulation current, we used an in silico approach. In our updated model, the outer layer's basolateral surface was provided with only Na+,K+-ATPases, Na+ conductance, and leak conductance. Under normal conditions, the circulation current was assumed to consist of K+ and be driven predominantly by Na+,K+-ATPases. The model replicated the experimentally measured electrochemical properties in all compartments of the lateral wall, and EP, under normal conditions and during blocking of Na+,K+-ATPases. Therefore, the circulation current across the outer layer's basolateral surface depends primarily on the three ion transport mechanisms. During the blockage, the reduced circulation current partially consisted of transiently evoked Na+ flow via the two conductances. This work defines the comprehensive system driving the circulation current.

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