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

Louis N Manganas,Sobia Akhtar,Dana E Antonucci,Claire R Campomanes,J Oliver Dolly,James S Trimmer

doi:10.1074/jbc.m109325200

Louis N Manganas, Sobia Akhtar + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m109325200

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Abstract

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel alpha-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 alpha- and Kv beta-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.

Highlights

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel ␣-subunit
We provide evidence that the nonsense mutation described in the patient with this novel drug-resistant form of EA-1 generates a Kv1.1 subunit with biochemical and cell biological properties distinct from wild-type Kv1.1 and from all other known EA-1 mutations
To investigate the molecular differences between Kv1.1 channels harboring these different EA-1 mutations, and how this contributes to the phenotypic variability in patients with this disease, site-directed mutagenesis was used to generate each of these mutations in rat Kv1.1

Summary

Introduction

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel ␣-subunit. We found that Kv1.1 with the EA-1 nonsense mutation exhibits a number of characteristic traits of misfolded membrane proteins and can confer this misfolded phenotype, with resultant intracellular retention, to co-assembled wild-type Kv1 ␣- and Kv␤-subunits.

Results

Conclusion