Properties of Heterochannels Kv(1.1-1.2)2 with Mutation T226R in the Kv1.1 Subunit

TL;DR

A mutation in the Kv1.1 protein affects potassium channels in the brain, leading to neurological disorders by altering channel function and membrane presentation.

Contribution

The study reveals how the T226R mutation in Kv1.1 affects heterochannels with Kv1.2, not just homotetramers, providing new insights into disease mechanisms.

Findings

Heterochannels with T226R mutation show slower activation and deactivation rates.

The mutation reduces membrane presentation of heterochannels but not their formation.

The T226R mutation has a stronger effect on homotetrameric Kv1.1 channels than on heterochannels.

Abstract

Mutation T226R in the Kv1.1 α-subunit of voltage-gated potassium Kv1 channels is associated with episodic ataxia type 1, severe neuromyotonia, and epilepsy. In vitro, this mutation was reported to considerably distort the functioning of homotetrameric channels Kv1.1; however, in the brain, Kv1.1 α-subunits form heterochannels predominantly associating with Kv1.2 α-subunits. Using the patch-clamp technique, fluorescent and Förster resonance energy transfer confocal microscopy, we revealed that heterochannels Kv(1.1(T226R)-1.2)2 formed by concatemers Kv1.1(T226R)-Kv1.2 in Neuro-2a cells have significantly slower activation and deactivation rates, and their activation occurs at a much less negative membrane potential compared to channels Kv(1.1-1.2)2 formed by concatemers Kv1.1-Kv1.2. This mutation does not noticeably affect the formation of complexes between α-subunits Kv1.1 and Kv1.2, but it does induce a delayed and possibly decreased presentation of heterochannels Kv(1.1(T226R)-1.2)2 on the plasma membrane. At the same time, the T226R mutation has a much stronger negative effect on the membrane presentation of homotetrameric Kv1.1 channels. Since heterochannels Kv1.1-Kv1.2 but not homotetrameric channels Kv1.1 are present in the brain, the heterochannels bearing mutation T226R are most likely underlying the pathogenesis of the disease by decreasing the responsiveness of cells to mild membrane depolarization and, thus, increasing the excitability of neurons.

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