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

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.

Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans

“…HEK293T cells expressing recSLC12A2 proteins carrying each of the three variants showed significantly decreased Cl − influx activity. Moreover, we observed abundant SLC12A2 signals in the basolateral membrane of strial marginal cells and lateral wall fibrocytes in non-human primate cochlea, a distribution identical to that reported for rodent cochleae [16], suggesting a conserved role for SLC12A2 in homeostasis of the endolymph by recycling K + from the perilymph to the stria vascularis in mammalian cochlea, including in humans [3,4]. The congenital, severe-to-profound hearing loss in our patients is consistent with the phenotype of Slc12a2-deficient M. musculus [16][17][18][19].…”

“…SLC12A2 is the entry site for Na + , K + , and 2Cl − from the intrastrial space to the strial marginal cells in the cochlear lateral wall [4]. Slc12a2-deficient M. musculus show loss of scala media [16][17][18][19], while homozygous Slc12a2 deficiency results in loss of endolymph volume, collapse of the otic vesicles with functional sensory hair cells, and a vestibular disorder phenotype in Danio rerio larvae [41].…”

“…Proper depolarization of hair cells is achieved via the influx of K + from the endolymph through a mechanotransduction channel located on the hair bundles in response to auditory stimuli. Production and maintenance of endolymph with a high K + concentration (> 150 mM) and endocochlear potential (> +80 mV) is primarily accomplished by the secretion of K + from the marginal cells of the stria vascularis in the cochlear lateral wall [3,4]. To achieve and maintain the unique composition of the endolymph, multiple energy-neutral ion transporters, such as Na + , K + , and 2Cl − cotransporters (NKCCs), are active in the lateral wall cells, along with active transport of K + by ion pumps, such as Na + , K + ATPases, and voltage-gated K + channels [3].…”

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

“…Despite continuing interest in SV cell types, an understanding of cellular heterogeneity, including a comprehensive understanding of SV cell type-specific transcriptional profiles, is incomplete. While several in vivo, in vitro, and in silico studies have identified key roles for particular strial cell types in EP generation, including MCs, ICs, and BCs (Takeuchi et al, 2000;Nin et al, 2008;Mori et al, 2009;Hibino et al, 2010;Chen and Zhao, 2014;Yoshida et al, 2015;Nin et al, 2017), the mechanisms by which the various cell types work together to accomplish EP generation as well as other strial functions remains largely undefined (Ohlemiller, 2009). Furthermore, the gene regulatory networks that provide the basis for these EP-generating mechanisms remain largely undefined.…”

Electrochemical properties of the non‐excitable tissue stria vascularis of the mammalian cochlea are sensitive to sounds

“…For in silico analysis (Fig. 2), the fibrocyte-integrated Nin-Hibino-Kurachi (fi-NHK) model developed in our earlier study was used (Nin et al 2017). Accordingly, the principles of the model described in this section are excerpted from the previous articles with the original authors' permission.…”