title: Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain.
abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant disorder characterized by continuous myokymia and episodic attacks of ataxia. Mutations in the gene KCNA1 that encodes the voltage-gated potassium channel Kv1.1 are responsible for EA1. In several brain areas, Kv1.1 coassembles with Kv1.4, which confers N-type inactivating properties to heteromeric channels. It is therefore likely that the rate of inactivation will be determined by the number of Kv1.4 inactivation particles, as set by the precise subunit stoichiometry. We propose that EA1 mutations affect the rate of N-type inactivation either by reduced subunit surface expression, giving rise to a reduced number of Kv1.1 subunits in heterotetramer Kv1.1-Kv1.4 channels, or by reduced affinity for the Kv1.4 inactivation domain. To test this hypothesis, quantified amounts of mRNA for Kv1.4 or Kv1.1 containing selected EA1 mutations either in the inner vestibule of Kv1.1 on S6 or in the transmembrane regions were injected into Xenopus laevis oocytes and the relative rates of inactivation and stoichiometry were determined. The S6 mutations, V404I and V408A, which had normal surface expression, reduced the rate of inactivation by a decreased affinity for the inactivation domain while the mutations I177N in S1 and E325D in S5, which had reduced subunit surface expression, increased the rate of N-type inactivation due to a stoichiometric increase in the number of Kv1.4 subunits.
authors.affiliation: Section of Human Physiology, Dept. of Internal Medicine, University of Perugia School of Medicine, Via del Giochetto, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grottesi
authors.forename: Andrea
authors.initials: A
authors.lastname: Biscarini
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D051662:Kv1.1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051665:Kv1.4 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014982:Xenopus laevis
chemical_list: D051663:Kv1.2 Potassium Channel; D051665:Kv1.4 Potassium Channel; D021122:Protein Subunits; D051662:Kv1.1 Potassium Channel