Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function.
Episodic ataxia type-1 syndrome (EA-1) is an autosomal dominant neurological disorder that manifests itself during infancy and results from point mutations in the voltage-gated potassium channel gene hKv1.1. The hallmark of the disease is continuous myokymia and episodic attacks of spastic contractions of the skeletal muscles, which cause permanent disability. Coexpression of hKv1.1 and hKv1.2 subunits produces heteromeric potassium channels with biophysical and pharmacological properties intermediate between the respective homomers. By using tandemly linked subunits, we demonstrate that hKv1.1 subunits bearing the EA-1 mutations V408A and E325D combine with hKv1.2 to produce channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. Moreover, hKv1.1V408A single-channel analysis reveals a approximately threefold reduction of the mean open duration of the channel compared with the wild-type, and this mutation alters the open-state stability of both homomeric and heteromeric channels. The results demonstrate that human Kv1.2 and Kv1.1 subunits coassemble to form a novel channel with distinct gating properties that are altered profoundly by EA-1 mutations, thus uncovering novel physiopathogenetic mechanisms of episodic ataxia type-1 myokymia syndrome.
D'Adamo
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MC
Istituto di Ricerche Farmacologiche [Mario Negri], Consorzio Mario Negri Sud, Department of Pharmacology and Molecular Pathology, Chieti, Italy.
Imbrici
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Sponcichetti
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Pessia
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D000818:Animals; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D051662:Kv1.1 Potassium Channel; D009154:Mutation; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013577:Syndrome; D014981:Xenopus
C496946:KCNA1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel