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Disease‐associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism
Author(s) -
Abbott Geoffrey W.,
Goldstein Steve A. N.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0520hyp
Subject(s) - mink , potassium channel , transmembrane domain , protein subunit , mutation , point mutation , herg , biology , mutant , microbiology and biotechnology , biophysics , genetics , chemistry , amino acid , biochemistry , gene , ecology
KCNE genes encode single transmembrane‐domain subunits, the MinK‐related peptides (MiRPs), which assemble with pore‐forming α subunits to establish the attributes of potassium channels in vivo. To investigate whether MinK, MiRP1, and MiRP2 operate similarly with their known native a subunit partners (KCNQ1, HERG, and Kv3.4, respectively) two conserved residues associated with human disease and influential in channel function were evaluated. As MiRPs assemble with a variety of α subunits in experimental cells and may do so in vivo, each peptide was also assessed with the other two α subunits. Inherited mutation of aspartate to asparagine (D → N) to yield D76N‐MinK is linked to cardiac arrhythmia and deafness;the analogs D82N‐MiRP1 and D90N‐MiRP2 were studied. Mutation of arginine to histidine (R → H) to yield R83H‐MiRP2 is associated with periodic paralysis; the analogs K69H‐MinK and K75H‐MiRP1 were also studied. Macroscopic and single‐channel currents showed that D → N mutations suppressed a subset of functions whereas R/K → H changes altered the activity of MinK, MiRP1, and MiRP2 with all three α subunits. The findings indicate that the KCNE peptides interact similarly with different α subunits and suggest a hypothesis: that clinical manifestations of inherited KCNE point mutations result from disruption of multiple native currents via promiscuous interactions.—Abbott, G. W., Goldstein, S. A. N. Disease‐associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 16, 390–400 (2002)