KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

Pablo Ávalos Prado, Stephanie Häfner, Yannick Comoglio, Brigitte Wdziekonski, Christophe Duranton, Bernard Attali, Jacques Barhanin, Guillaume Sandoz

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)534-544.e11
JournalCell
Volume184
Issue number2
DOIs
StatePublished - 21 Jan 2021

Keywords

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

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