The role of an inwardly rectifying K(+) channel (Kir4.1) in the inner ear and hearing loss

Abstract

The KCNJ10 gene which encodes an inwardly rectifying K(+) channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with EAST or SeSAME syndromes. This review mainly focuses on the expression and function of Kir4.1 potassium channels in the inner ear and hearing. We first introduce general information about inwardly rectifying potassium (Kir) channels. Then, we review the expression and function of Kir4.1 channels in the inner ear, especially in endocochlear potential (EP) generation. Finally, we review KCNJ10 mutation-induced hearing loss and functional impairments. Kir4.1 is strongly expressed on the apical membrane of intermediate cells in the stria vascularis and in the satellite cells of cochlear ganglia. Functionally, Kir4.1 has critical roles in cochlear development and hearing through two distinct aspects of extracellular K(+) homeostasis: First, it participates in the generation and maintenance of EP and high K(+) concentration in the endolymph inside the scala media. Second, Kir4.1 is the major K(+) channel in satellite glial cells surrounding spiral ganglion neurons to sink K(+) ions expelled by the ganglion neurons during excitation. Kir4.1 deficiency leads to hearing loss with the absence of EP and spiral ganglion neuron degeneration. Deafness mutants show loss-of-function and reduced channel membrane-targeting and currents, which can be rescued upon by co-expression with wild-type Kir4.1. This review provides insights for further understanding Kir potassium channel function in the inner ear and the pathogenesis of deafness due to KCNJ10 deficiency, and also provides insights for developing therapeutic strategies targeting this deafness.

Keywords: EAST; KCNJ10; SeSAME; deafness; endocochlear potential; spiral ganglion.

Fig. 1

Expression of Kir4.1 in the cochlear lateral wall. A–B: Schematic drawing of the cochlea and the cochlear lateral wall. C-E: Kir4.1 labeling in the intermediate cells in the cochlear lateral wall. The basal cells are visible by Pannexin2 (Panx2) labeling (red) (Wang et al., 2009). Note that the basal cells have no Kir4.1 labeling (green). SV: stria vascularis; SPL: spiral ligament. Scale bar: 25 µm.

Fig. 2

Schematic drawing of “two-cell” model for EP generation. Intermediate cells (IC), basal cells (BC) and fibrocytes (FC) are coupled by gap junctions (GJ) acting as one cell. Marginal cells (MC) act as another cell. Na⁺, K⁺-ATPase and Na⁺, K⁺, 2Cl⁻-cotransporter are located at the bottom of the FCs to pump K⁺ ions into cells leading to cells depolarizing. Kir4.1 is located at the apical membrane of the ICs facing to the intrastrial space (IS) to generate positive EP.

Fig. 3

Predicted structure of the Kir4.1 channel and locations of mutations. A: Sequence alignment of human Kir4.1 (P78508.1) with hKir1.1 (P48048.1), hKir2.1 (P63252.1), hKir3.1 (P48549.1), hKir5.1 (Q9NPI9.1), hKir6.2 (Q14654.2), and hKir7.1 (O60928.1). B: A Kir4.1 subunit consists of two transmembrane domains (TM1 and TM2) that flank a K⁺-selective pore (F). A functional channel is assembled by 4 subunits. Only two are displayed for clarity. Modified from Sala-Rabanal et al., 2010.