Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss

Yanhong Gao, Sergey Yechikov, Ana E. Vázquez, Dongyang Chen, Liping Nie

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

KCNQ4, a voltage-gated potassium channel, plays an important role in maintaining cochlear ion homoeostasis and regulating hair cell membrane potential, both essential for normal auditory function. Mutations in the KCNQ4 gene lead to DFNA2, a subtype of autosomal dominant non-syndromic deafness that is characterized by progressive sensorineural hearing loss across all frequencies. Despite recent advances in the identification of pathogenic KCNQ4 mutations, the molecular aetiology of DFNA2 remains unknown. We report here that decreased cell surface expression and impaired conductance of the KCNQ4 channel are two mechanisms underlying hearing loss in DFNA2. In HEK293T cells, a dramatic decrease in cell surface expression was detected by immunofluorescent microscopy and confirmed by Western blot for the pathogenic KCNQ4 mutants L274H, W276S, L281S, G285C, G285S, G296S and G321S, while their overall cellular levels remained normal. In addition, none of these mutations affected tetrameric assembly of KCNQ4 channels. Consistent with these results, all mutants showed strong dominant-negative effects on the wild-type (WT) channel function. Most importantly, overexpression of HSP90β, a key component of the molecular chaperone network that controls the KCNQ4 biogenesis, significantly increased cell surface expression of the KCNQ4 mutants L281S, G296S and G321S. KCNQ4 surface expression was restored or considerably improved in HEK293T cells mimicking the heterozygous condition of these mutations in DFNA2 patients. Finally, our electrophysiological studies demonstrated that these mutations directly compromise the conductance of the KCNQ4 channel, since no significant change in KCNQ4 current was observed after KCNQ4 surface expression was restored or improved.

Original languageEnglish (US)
Pages (from-to)889-900
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume17
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Sensorineural Hearing Loss
Mutation
Voltage-Gated Potassium Channels
Molecular Chaperones
Cochlea
Deafness
Hearing Loss
Membrane Potentials
Microscopy
Homeostasis
Western Blotting
Cell Membrane
Ions
Genes

Keywords

  • Hearing loss
  • KCNQ4
  • Molecular chaperone
  • Mutations
  • Potassium channel
  • Surface expression
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. / Gao, Yanhong; Yechikov, Sergey; Vázquez, Ana E.; Chen, Dongyang; Nie, Liping.

In: Journal of Cellular and Molecular Medicine, Vol. 17, No. 7, 07.2013, p. 889-900.

Research output: Contribution to journalArticle

Gao, Yanhong ; Yechikov, Sergey ; Vázquez, Ana E. ; Chen, Dongyang ; Nie, Liping. / Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. In: Journal of Cellular and Molecular Medicine. 2013 ; Vol. 17, No. 7. pp. 889-900.
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