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.

Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

“…The models that are presented in this work can be useful for studying these emergent properties in normal physiological Purkinje neurons, as well as in ataxia . Future studies can be developed to study spontaneous Purkinje neuron firing rate or precision of spike timing and interspike intervals in various classes of ataxias with mutations in genes that code for calcium channels [9,76-78] and potassium channels [65,79], as well as IP3R1 or related proteins (including SCA1, SCA2, SCA3, SCA15/16) [3,4,6,7,9-16]. …”

“…These models employ several novel concepts and approaches and provide a framework for the study not only of IP3R1-associated ataxias , but of various SCAs involving mutations of other molecules in the model, such as potassium channels [65,79,101,102] and calcium channels [29,76,77,103]. …”

Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4‐1.1/Kvβ1.1 and Kv1.4‐1.1/Kvβ1.2

“…The I177N mutation, which is located within the S1 segment, causes similar defects in fast inactivation. In a previous study, we showed that the I177N mutation accelerates approximately fourfold the deactivation kinetics of the channel, shifts the voltage dependence of activation by ∼60 mV to more depolarized potentials and reduces ∼2.6‐fold the mean open duration of the channel (Imbrici et al. , 2003).…”

Animal Models of Episodic Ataxia Type 1 (EA1)

“…The molecular mechanisms underlying EA1 have been established by determining the functional properties of wild-type (WT) and several mutant channels in Xenopus oocytes or mammalian cell lines (Adelman et al, 1995;D'Adamo et al, 1998;Zerr et al, 1998;D'Adamo et al, 1999;Zuberi et al, 1999;Eunson et al, 2000;Manganas et al, 2001;Cusimano et al, 2004;Imbrici et al, 2003Imbrici et al, , 2007Imbrici et al, , 2008Imbrici et al, , 2006Imbrici et al, , 2007Imbrici et al, , 2008Imbrici et al, , 2009 (Petersson et al, 2003); S309T is a missense mutation identified in autosomal-dominant myokymia and seizures rats: rKv1.1 S309T/+ (Ishida et al, 2012); V408A is a mutation identified in individuals with EA1 that was inserted into the murine Kcna1 to generate a knockin animal model of the disease: mKv1.1 V408A/+ (Herson et al, 2003).…”