Conservation of Hearing by Simultaneous Mutation of Na,K-ATPase and NKCC1

Abstract

Although drug-induced and age-related hearing losses are frequent otologic problems affecting millions of people, their underlying mechanisms remain uncertain. The inner ear is exclusively endowed with a positive endocochlear potential (EP) that serves as the main driving force for the generation of receptor potential in hair cells to confer hearing. Deterioration of EP leads to hearing loss or deafness. The generation of EP relies on the activity of many ion transporters to establish active potassium (K + ) cycling within the inner ear, including K + channels, the Na-K-2Cl co-transporter (NKCC1), and the a 1 and a 2 isoforms of Na,K-ATPase. We show that heterozygous deletion of either NKCC1, a 1 -Na,K-ATPase, or a 2 -Na,K-ATPase independently results in progressive, age-dependent hearing loss with minimal alteration in cochlear morphology. Double heterozygote deletion of NKCC1 with a 1 -Na,K-ATPase also shows a progressive, though delayed, age-dependent hearing loss. Remarkably, double heterozygote deletion of NKCC1 with a 2 -Na,K-ATPase demonstrates a striking preservation of hearing threshold both initially and with age. Measurements of the EP confirm the anticipated drop in potential for genotypes that demonstrate age-dependent hearing loss. The EP generated by the NKCC1 + a 2 -Na,K-ATPase double heterozygote, however, is maintained at a level comparable to that of the control condition, suggesting a potential advantage in this combination of ion transporter modification. These observations provide insight into the detailed mechanisms of EP generation, and results of combination-knockout experiments may have important implications in the future treatment of drug-induced and age-related hearing losses.

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

“…Although homozygous deletion of either NKAα1 or NKAα2 is lethal at birth, heterozygous deletions are viable (Moseley et al 2007). Despite normal cochlear morphology, NKAα1 +/− and NKAα2 +/− mice show reductions in the endocochlear potential and progressive, age-dependent hearing loss (Diaz et al 2007). A possible neuronal contribution to hearing loss in these mice has not been excluded.…”

Critical Roles of Transitional Cells and Na/K-ATPase in the Formation of Vestibular Endolymph

“…Absorbed K ϩ may leak in the perilymph through background K ϩ channels that remain to be characterized. However, since transitional cells still express NKCC1 and Na/K-ATPase, they may mask their secreting potential by means of a currently unknown mechanism (indicated with a question mark ing the cochlear endolymph (Diaz et al, 2007). Last, coadministration of ouabain and bumetanide failed to increase [K ϩ ]ec inhibition, indicating that the pump drives NKCC1 (Table 1).…”

Divergent Aging Characteristics in CBA/J and CBA/CaJ Mouse Cochleae

“…In this and other mouse models we have examined, we have interpreted reduced marginal cell density as an indication that critical marginal cell functions in generating the EP are impaired. We suppose-but have yet to show-that fewer, larger, marginal cells maintain fewer critical pumps, transporters, and channels , or alter the critical 'stoichiometry' of these among strial cell types (Diaz et al 2007). We have not proposed or observed that marginal cell degeneration leaves exposed intermediate cells or alters the ion barrier of scala media.…”