KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

Cell. 2021 Jan 21;184(2):534-544.e11. doi: 10.1016/j.cell.2020.11.047. Epub 2020 Dec 28.


Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.

Keywords: IsK; KCNE1; MinK1; ancillary subunits; anoctamin; potassium channel; protein complexes; proximal convoluted tubule cells; single molecule fluorescence; voltage-dependent ion channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoctamin-1 / metabolism
  • Calcium / metabolism
  • Chloride Channels / metabolism
  • HEK293 Cells
  • Humans
  • Kidney Tubules, Proximal / metabolism
  • Mice
  • Mutant Proteins / metabolism
  • Peptides / metabolism
  • Polymorphism, Genetic
  • Potassium Channels, Voltage-Gated / chemistry
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism*
  • Protein Binding
  • Protein Domains
  • Protein Subunits / metabolism*
  • Renin-Angiotensin System


  • Anoctamin-1
  • Chloride Channels
  • KCNE1 protein, human
  • Kcne1 protein, mouse
  • Mutant Proteins
  • Peptides
  • Potassium Channels, Voltage-Gated
  • Protein Subunits
  • Calcium