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

F. Nin,Takamasa Yoshida,Shingo Murakami,Genki Ogata,S. Uetsuka,Samuel Choi,K. Doi,Seishiro Sawamura,H. Inohara,S. Komune,Y. Kurachi,H. Hibino

Published 2017 in npj Systems Biology and Applications

ABSTRACT

The cochlear lateral wall—an epithelial-like tissue comprising inner and outer layers—maintains +80 mV in endolymph. This endocochlear potential supports hearing and represents the sum of all membrane potentials across apical and basolateral surfaces of both layers. The apical surfaces are governed by K+ equilibrium potentials. 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 endocochlear potential, 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. In in vivo mammalian cochlea, ionic current constantly and unidirectionally flows—this unique “circulation current”, which contributes to high sensitivity of sensory cells transducing atomic scale acoustic vibrations to electrical signals, likely depends upon ion transports across a multiple-layered epithelial tissue. To determine how the circulation current is established, a team conducted by Hiroshi Hibino at Niigata University in Japan used a theoretical approach, because ionic currents are unmeasurable in vivo. A conceptual computational model they previously developed lacked involvement of an epithelial tissue membrane recently found to show unusual ion transport profile; integration and coupling of this element to other membrane transport machineries resulted in reproducing experimental measurements. This work defines the comprehensive system driving the circulation current, which remains uncertain for nearly 20 years, and helps us to understand the mechanism for hearing.

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