KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity

J Cell Physiol. 2019 Aug;234(8):13361-13369. doi: 10.1002/jcp.28013. Epub 2019 Jan 5.


Transmembrane channel-like protein isoform 1 (TMC1) is essential for the generation of mechano-electrical transducer currents in hair cells of the inner ear. TMC1 disruption causes hair cell degeneration and deafness in mice and humans. Although thought to be expressed at the cell surface in vivo, TMC1 remains in the endoplasmic reticulum when heterologously expressed in standard cell lines, precluding determination of its roles in mechanosensing and pore formation. Here, we report that the KCNQ1 Kv channel forms complexes with TMC1 and rescues its surface expression when coexpressed in Chinese Hamster Ovary cells. TMC1 rescue is specific for KCNQ1 within the KCNQ family, is prevented by a KCNQ1 trafficking-deficient mutation, and is influenced by KCNE β subunits and inhibition of KCNQ1 endocytosis. TMC1 lowers KCNQ1 and KCNQ1-KCNE1 K+ currents, and despite the surface expression, it does not detectably respond to mechanical stimulation or high salt. We conclude that TMC1 is not intrinsically mechano- or osmosensitive but has the capacity for cell surface expression, and requires partner protein(s) for surface expression and mechanosensitivity. We suggest that KCNQ1, expression of which is not thought to overlap with TMC1 in hair cells, is a proxy partner bearing structural elements or a sequence motif reminiscent of a true in vivo TMC1 hair cell partner. Discovery of the first reported strategy to rescue TMC1 surface expression should aid future studies of the TMC1 function and native partners.

Keywords: Kv7.1; potassium channel; transmembrane channel-like protein isoform 1 (TMC1).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • CHO Cells
  • COS Cells
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cricetulus
  • Female
  • Hair Cells, Auditory, Inner / metabolism
  • Humans
  • KCNQ1 Potassium Channel / chemistry
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / metabolism*
  • Mechanotransduction, Cellular / genetics
  • Mechanotransduction, Cellular / physiology
  • Membrane Potentials
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mutagenesis, Site-Directed
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels, Voltage-Gated / chemistry
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Xenopus laevis


  • KCNE1 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Membrane Proteins
  • Potassium Channels, Voltage-Gated
  • Recombinant Proteins
  • TMC1 protein, human