title: The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome.
abstract: N-terminal mutations in the KCNQ1 channel are frequently linked to fatal 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.
authors.affiliation: Inserm, U533, Nantes, France.
authors.forename: Shehrazade
authors.initials: S
authors.lastname: Dahimène
authors.forename: Sébastien
authors.initials: S
authors.lastname: Alcoléa
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Philippe
authors.initials: P
authors.lastname: Jourdon
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Robert
authors.initials: R
authors.lastname: Brasseur
authors.forename: Annick
authors.initials: A
authors.lastname: Thomas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baró
authors.forename: Jean
authors.initials: J
authors.lastname: Mérot
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006388:Hemagglutinins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D006388:Hemagglutinins; D051657:KCNQ1 Potassium Channel; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins