Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties.
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.
Manganas
L N
LN
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794, USA.
Akhtar
S
S
Antonucci
D E
DE
Campomanes
C R
CR
Dolly
J O
JO
Trimmer
J S
JS
D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D019556:COS Cells; D006801:Humans; D051662:Kv1.1 Potassium Channel; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology*; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
C496946:KCNA1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D025801:Ubiquitin; D014746:Vimentin; D051662:Kv1.1 Potassium Channel