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Abstract <p><b>Objective:</b> Mutation A261T in the Kv1.1 α-subunit of voltage-gated potassium channels Kv1 is associated with episodic ataxia type 1, myokymia, and epileptic syndrome. The mutation enhances the function of homotetrameric Kv1.1 channels, promoting their premature opening and, as a consequence, leading to hyperpolarization of the cell membrane. To clarify the molecular mechanisms underlying the phenotypic manifestation of this mutation in patients, the properties of mutant heterochannels Kv(1.1(A261T)–1.2)<sub>2</sub>, which are the main form of presentation of the Kv1.1 α-subunit in the central nervous system, were studied. <b>Methods:</b> Confocal microscopy, the Förster resonance energy transfer method and electrophysiological techniques were used to study the properties of the mutant Kv1.1(A261T) α-subunit, homotetrameric Kv1.1(A261T) channels, as well as heterochannels Kv(1.1(A261T)–1.2)<sub>2</sub> formed by concatemers Kv1.1(A261T)–Kv1.2, which were expressed in mice neuroblastoma Neuro-2a cells. <b>Results and Discussion:</b> It was found that the A261T mutation accelerated the incorporation of homotetrameric channels Kv1.1(A261T) into the plasma membrane of cells. The mutation did not interfere with the channel binding to peptide blockers and did not impair the ability of α-subunits Kv1.1(A261T) to form heterochannels Kv1.1/Kv1.2. The mutant heterochannels Kv(1.1(A261T)–1.2)<sub>2</sub> exhibited a significant decrease in the membrane potential that activated the channels, as well as accelerated activation and deactivation kinetics compared to heterochannels without the mutation. The peptide blockers hongotoxin 1 and Ce4 retained high affinity for mutant heterochannels and significantly reduced currents through these channels. <b>Conclusions:</b> The data obtained suggest that the gain-of-function effect of the A261T mutation is preserved in heterochannels Kv(1.1(A261T) –1.2)<sub>2</sub> but is reduced as compared to homotetrameric channels Kv1.1(A261T). Thus, the altered properties of the mutant heterochannels may underlie the phenotypic manifestations of this mutation, as well as the development of the pathology of the nervous system. High-affinity peptide blockers may facilitate the studies of mutant heterochannels in neurons and the development of therapeutic agents for these types of channelopathies.</p>

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Influence of Mutant Alpha-Subunit Kv1.1(A261T) on the Properties of the Heterotetrameric Channel Kv1.1-Kv1.2

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • A. V. Efremenko,
  • I. Dzhumaniiazova,
  • D. V. Abramochkin,
  • I. I. Shmatin,
  • V. N. Korabeynikova,
  • E. V. Kryukova,
  • M. P. Kirpichnikov,
  • A. V. Feofanov,
  • O. V. Nekrasova

摘要

Abstract

Objective: Mutation A261T in the Kv1.1 α-subunit of voltage-gated potassium channels Kv1 is associated with episodic ataxia type 1, myokymia, and epileptic syndrome. The mutation enhances the function of homotetrameric Kv1.1 channels, promoting their premature opening and, as a consequence, leading to hyperpolarization of the cell membrane. To clarify the molecular mechanisms underlying the phenotypic manifestation of this mutation in patients, the properties of mutant heterochannels Kv(1.1(A261T)–1.2)2, which are the main form of presentation of the Kv1.1 α-subunit in the central nervous system, were studied. Methods: Confocal microscopy, the Förster resonance energy transfer method and electrophysiological techniques were used to study the properties of the mutant Kv1.1(A261T) α-subunit, homotetrameric Kv1.1(A261T) channels, as well as heterochannels Kv(1.1(A261T)–1.2)2 formed by concatemers Kv1.1(A261T)–Kv1.2, which were expressed in mice neuroblastoma Neuro-2a cells. Results and Discussion: It was found that the A261T mutation accelerated the incorporation of homotetrameric channels Kv1.1(A261T) into the plasma membrane of cells. The mutation did not interfere with the channel binding to peptide blockers and did not impair the ability of α-subunits Kv1.1(A261T) to form heterochannels Kv1.1/Kv1.2. The mutant heterochannels Kv(1.1(A261T)–1.2)2 exhibited a significant decrease in the membrane potential that activated the channels, as well as accelerated activation and deactivation kinetics compared to heterochannels without the mutation. The peptide blockers hongotoxin 1 and Ce4 retained high affinity for mutant heterochannels and significantly reduced currents through these channels. Conclusions: The data obtained suggest that the gain-of-function effect of the A261T mutation is preserved in heterochannels Kv(1.1(A261T) –1.2)2 but is reduced as compared to homotetrameric channels Kv1.1(A261T). Thus, the altered properties of the mutant heterochannels may underlie the phenotypic manifestations of this mutation, as well as the development of the pathology of the nervous system. High-affinity peptide blockers may facilitate the studies of mutant heterochannels in neurons and the development of therapeutic agents for these types of channelopathies.