Disease-linked supertrafficking of a potassium channel

Gain-of-function (GOF) mutations in the voltage-gated potassium channel subfamily Q member 1 (KCNQ1) can induce cardiac arrhythmia. In this study, it was tested whether any of the known human GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface—“supertrafficking.” Seven of the 15 GOF mutants tested were seen to surface traffic more efficiently than the WT channel. Among these, we found that the levels of R231C KCNQ1 in the plasma membrane were fivefold higher than the WT channel. This was shown to arise from the combined effects of enhanced efficiency of translocon-mediated membrane integration of the S4 voltage-sensor helix and from enhanced post-translational folding/trafficking related to the energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with the voltage-gated potassium channel-regulatory subfamily E member 1 not only exhibited constitutive conductance but also revealed that the single-channel activity of this mutant is only 20% that of WT. The GOF phenotype associated with R231C therefore reflects the effects of supertrafficking and constitutive channel activation, which together offset reduced channel activity. These investigations show that membrane protein supertrafficking can contribute to human disease.