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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.

SUBMITTER: Chen J

PROVIDER: S-EPMC4007161 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Chen J J Zhao H-B HB

Neuroscience 20140128

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 ...[more]

PMID: 24480364

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Project description:BACKGROUND:Neurosteroids have various physiological and neuropsychopharmacological effects. In addition to the genomic effects of steroids, some neurosteroids modulate several neurotransmitter receptors and channels, such as N-methyl-D-aspartate receptors, gamma-aminobutyric acid type A (GABA(A)) receptors, and sigma(1) receptors, and voltage-gated Ca(2+) and K(+) channels. However, the molecular mechanisms underlying the various effects of neurosteroids have not yet been sufficiently clarified. In the nervous system, inwardly rectifying K(+) (Kir) channels also play important roles in the control of resting membrane potential, cellular excitability and K(+) homeostasis. Among constitutively active Kir2 channels in a major Kir subfamily, Kir2.3 channels are expressed predominantly in the forebrain, a brain area related to cognition, memory, emotion, and neuropsychiatric disorders. METHODOLOGY/PRINCIPAL FINDINGS:The present study examined the effects of various neurosteroids on Kir2.3 channels using the Xenopus oocyte expression assay. In oocytes injected with Kir2.3 mRNA, only pregnenolone sulfate (PREGS), among nine neurosteroids tested, reversibly potentiated Kir2.3 currents. The potentiation effect was concentration-dependent in the micromolar range, and the current-voltage relationship showed inward rectification. However, the potentiation effect of PREGS was not observed when PREGS was applied intracellularly and was not affected by extracellular pH conditions. Furthermore, although Kir1.1, Kir2.1, Kir2.2, and Kir3 channels were insensitive to PREGS, in oocytes injected with Kir2.1/Kir2.3 or Kir2.2/Kir2.3 mRNA, but not Kir2.1/Kir2.2 mRNA, PREGS potentiated Kir currents. These potentiation properties in the concentration-response relationships were less potent than for Kir2.3 channels, suggesting action of PREGS on Kir2.3-containing Kir2 heteromeric channels. CONCLUSIONS/SIGNIFICANCE:The present results suggest that PREGS acts as a positive modulator of Kir2.3 channels. Kir2.3 channel potentiation may provide novel insights into the various effects of PREGS.

Dataset Information

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

Publications

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

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