Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels

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 similar to17-fold the current amplitude, accelerates similar to4-fold the deactivation kinetics of the channel and shifts the voltage dependence of activation similar to60 mV to more depolarized potentials. Single-channel recordings also showed that the mean open duration of 1177N channels was similar to2.6-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 1177N mutation. Furthermore, the data suggest that the 1177N substitution may alter the gating properties of the channel that are specifically defined by the S1 segment.