The N-Terminal Juxtamembranous Domain Of Kcnq1 Is Critical For Channel Surface Expression - Implications In The Romano-Ward Lqt1 Syndrome

arrhythmias in newborn children and adolescents but the cellular mechanisms
involved in this dramatic issue remain, however, to be discovered. Here, we
analyzed the trafficking of a series of N-terminal truncation mutants and
identified a critical trafficking motif of KCNQ1. This determinant is located in
the juxtamembranous region preceding the first transmembrane domain of the
protein. Three mutations (Y111C, L114P and P117L) implicated in inherited
Romano-Ward LQT1 syndrome, are embedded within this domain. Reexpression studies
in both COS-7 cells and cardiomyocytes showed that the mutant proteins fail to
exit the endoplasmic reticulum. KCNQ1 subunits harboring Y111C or L114P exert a
dominant negative effect on the wild-type KCNQ1 subunit by preventing plasma
membrane trafficking of heteromultimeric channels. The P117L mutation had a less
pronounced effect on the trafficking of heteromultimeric channels but altered the
kinetics of the current. Furthermore, we showed that the trafficking determinant
in KCNQ1 is structurally and functionally conserved in other KCNQ channels and
constitutes a critical trafficking determinant of the KCNQ channel family.
Computed structural predictions correlated the potential structural changes
introduced by the mutations with impaired protein trafficking. In conclusion, our
studies unveiled a new role of the N-terminus of KCNQ channels in their
trafficking and its implication in severe forms of LQT1 syndrome.