Episodic Ataxia Type-1 Mutations in the Kv1.1 Potassium Channel Display Distinct Folding and Intracellular Trafficking Properties

• Published in: The Journal of biological chemistry Vol. 276; no. 52; pp. 49427 - 49434
• Main Authors: Manganas, Louis N., Akhtar, Sobia, Antonucci, Dana E., Campomanes, Claire R., Dolly, J. Oliver, Trimmer, James S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.12.2001; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Ataxia - genetics; Ataxia - physiopathology; COS Cells; Humans; Kv1.1 Potassium Channel; Mutation; Neurons - physiology; Phenotype; Potassium Channels - chemistry; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Protein Folding; Protein Transport - physiology; Rats; Ubiquitin - metabolism; Vimentin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109325200

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel α-subunit. EA-1 patients exhibit substantial phenotypic variability resulting from at least 14 distinct EA-1 point mutations. We found that EA-1 missense mutations generate mutant Kv1.1 subunits with folding and intracellular trafficking properties indistinguishable from wild-type Kv1.1. However, the single identified EA-1 nonsense mutation exhibits intracellular aggregation and detergent insolubility. This phenotype can be transferred to co-assembled Kv1 α- and Kvβ-subunits associated with Kv1.1 in neurons. These results suggest that as in many neurodegenerative disorders, intracellular aggregation of misfolded Kv1.1-containing channels may contribute to the pathophysiology of EA-1.