TY - JOUR
T1 - KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies
AU - Ávalos Prado, Pablo
AU - Häfner, Stephanie
AU - Comoglio, Yannick
AU - Wdziekonski, Brigitte
AU - Duranton, Christophe
AU - Attali, Bernard
AU - Barhanin, Jacques
AU - Sandoz, Guillaume
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1/21
Y1 - 2021/1/21
N2 - 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.
AB - 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.
KW - IsK
KW - KCNE1
KW - MinK1
KW - ancillary subunits
KW - anoctamin
KW - potassium channel
KW - protein complexes
KW - proximal convoluted tubule cells
KW - single molecule fluorescence
KW - voltage-dependent ion channels
UR - http://www.scopus.com/inward/record.url?scp=85099310986&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.11.047
DO - 10.1016/j.cell.2020.11.047
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C2 - 33373586
AN - SCOPUS:85099310986
SN - 0092-8674
VL - 184
SP - 534-544.e11
JO - Cell
JF - Cell
IS - 2
ER -
