Abstract
KCNE genes encode single transmembrane-domain subunits, the MinK-related peptides (MiRPs), which assemble with pore-forming alpha subunits to establish the attributes of potassium channels in vivo. To investigate whether MinK, MiRP1, and MiRP2 operate similarly with their known native alpha 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 alpha subunits in experimental cells and may do so in vivo, each peptide was also assessed with the other two alpha 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 alpha subunits. The findings indicate that the KCNE peptides interact similarly with different alpha subunits and suggest a hypothesis: that clinical manifestations of inherited KCNE point mutations result from disruption of multiple native currents via promiscuous interactions.
Highlights
Classical voltage-gated potassium channels contain four pore-forming (α) subunits that supply domains that sense and respond to voltage and mediate ion permeation (1)
Inherited mutations in MinK are associated with cardiac arrhythmia and deafness (9 – 12), those in MinKrelated peptide 1 (MiRP1) with inherited and drug-induced cardiac arrhythmia (7, 13), and those in MiRP2 have been linked to periodic paralysis (8)
Sequence alignment of MinK, MiRP1, and MiRP2 indicates that D76-MinK is a conserved residue (Fig. 1); a homologous D is present in MiRP4 but not MiRP3 (3)
Summary
Classical voltage-gated potassium channels contain four pore-forming (α) subunits that supply domains that sense and respond to voltage and mediate ion permeation (1). The KCNE2 product MinKrelated peptide 1 (MiRP1) assembles with the α subunit HERG to generate a current resembling cardiac IKr (7) and the KCNE3 product MiRP2 combines with the Kv3.4 α subunit to form a subthreshold, A-type channel in skeletal muscle (8). MinK has been found to assemble with KCNQ1 (5, 6) and with HERG (14); MiRP1 combines with HERG (7, 15), but with Kv4.2 (16, 17) and perhaps HCN1 (18); and MiRP2 associates with Kv3.4 (8) but with KCNQ1 and HERG (19, 20) Whereas such observations suggest that α subunits in native cells may rarely function alone (21), these varied partnerships have not yet been demonstrated in vivo. The idea that KCNE peptides can alter the function of more than one α subunit type suggests they might operate in different complexes in similar fashion, presumably via common subunit-subunit
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