Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1

Abstract

Kv1.1 voltage-gated potassium channels serve as key regulators of neuronal function and mutations in Kv1.1 lead to the human movement and epilepsy-related disorder, Episodic Ataxia type-1 (EA1). Transcripts encoding Kv1.1 may be modified by a site-specific adenosine-to-inosine RNA editing event, leading to the expression of an altered protein with an isoleucine to valine change at amino acid 400 (I400V). The non-edited [Kv1.1(I)] and edited [Kv1.1(V)] channels display altered functions in heterologous expression systems, but their significance in normal physiology and with regard to EA1 have not been characterized. We have developed new mouse models which solely express either the non-edited [Kv1.1(I)] or edited [Kv1.1(V)] isoforms of the channel. Our studies have revealed that both mice display conditional postnatal lethality and that the non-edited [Kv1.1(I)] mice exhibit an EA1-like disorder, stress-induced motor dyscoordination. In addition, we observed that editing altered drug-induced seizure-susceptibility for these mutant mouse models. Mice expressing the non-edited [Kv1.1(I)] channel exhibited a lowered threshold for drug-induced seizures, whereas mutant animals expressing the edited [Kv1.1(V)] channel exhibited an increased threshold. To further characterize the collective effects of Kv1.1 editing in transcripts containing human EA1 mutations, we discovered that three mutations (V404I, I407M, and V408A), in close proximity to the editing site, decreased Kv1.1 RNA editing in vitro. Utilizing the V408A/+ mouse model of EA1, we confirmed that the V408A mutation leads to decreases in Kv1.1 RNA editing in vivo. Electrophysiological characterization of the edited EA1 mutant channels also indicated that these channel isoforms display channel dysfunctions unique to each mutation, as compared to their respective non-edited EA1 channels. Thus, Kv1.1 RNA editing has a substantial impact on normal physiology and may be dysregulated in the EA1 disorder, as well as contribute to the wide variety in symptom severity observed in EA1 patients.