title: Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels.
abstract: Voltage-gated potassium channels (Kv) play important roles in neurotransmission, nerve cell excitability and disease. Several missense mutations in the Kv1.1 gene have been associated with episodic ataxia type-1 syndrome (EA-1), which is characterized by continuous myokymia, episodic attacks of ataxic gait and spastic contractions of skeletal muscles. In this study we show that I177N, an EA-1 mutation located in S1 segment, alters the expression and gating properties of the channel expressed in Xenopus oocytes. In particular, it reduces ~17-fold the current amplitude, accelerates ~4-fold the deactivation kinetics of the channel and shifts the voltage dependence of activation ~60 mV to more depolarized potentials. Single-channel recordings also showed that the mean open duration of I177N channels was ~2.6-fold smaller than the wild-type. These results demonstrate that both reduced current levels and specific gating defects are the likely causes of EA-1 symptoms in patients bearing the I177N mutation. Furthermore, the data suggest that the I177N substitution may alter the gating properties of the channel that are specifically defined by the S1 segment.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri Consorzio, Mario Negri Sud, I-66030 Santa Maria Imbaro (Chieti), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Antonella
authors.initials: A
authors.lastname: Cusimano
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.forename: Amalia
authors.initials: A
authors.lastname: De Curtis
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001216:Asparagine / Q000235:genetics; D055592:Biophysical Phenomena; D001703:Biophysics; D002524:Cerebellar Ataxia / Q000235:genetics*; D004553:Electric Conductivity; D006801:Humans; D015640:Ion Channel Gating; D007532:Isoleucine / Q000235:genetics; D007700:Kinetics; D051662:Kv1.1 Potassium Channel; D009154:Mutation / Q000235:genetics; D009865:Oocytes; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D014982:Xenopus laevis
chemical_list: C496946:KCNA1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D007532:Isoleucine; D051662:Kv1.1 Potassium Channel; D001216:Asparagine