Disease-linked super-trafficking of a potassium channel.

Abstract Gain-of-function (GOF) mutations in the KCNQ1 voltage-gated potassium channel can induce cardiac arrhythmia. Here 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—"super-trafficking". Seven out of the 15 GOF mutants tested were seen to surface-traffic more efficiently than the wild type (WT) channel. Among these we found that levels of R231C KCNQ1 in the plasma membrane were 5-fold 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 that is related to energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with KCNE1 exhibits 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 super-trafficking and constitutive channel activation, which together offset reduced channel activity. These investigations show that membrane protein super-trafficking can contribute to human disease.