title: The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels.
abstract: Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.
authors.affiliation: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Szu-Han
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ssu-Ju
authors.initials: SJ
authors.lastname: Fu
authors.affiliation: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jing-Jia
authors.initials: JJ
authors.lastname: Huang
authors.affiliation: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Yung
authors.initials: CY
authors.lastname: Tang
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D003062:Codon; D005260:Female; D015870:Gene Expression; D006801:Humans; D015640:Ion Channel Gating; D051662:Kv1.1 Potassium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051665:Kv1.4 Potassium Channel / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D020385:Myokymia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D014176:Protein Biosynthesis; D055503:Protein Multimerization; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D003062:Codon; D051665:Kv1.4 Potassium Channel; D051662:Kv1.1 Potassium Channel