Modulation of Closed−State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4−AP Induced Potentiation

@article{Stas2015ModulationOC,
 title={Modulation of Closed−State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4−AP Induced Potentiation},
 author={Jeroen I. Stas and Elke Bocksteins and Alain J. Labro and Dirk J Snyders},
 journal={PLoS ONE},
 year={2015},
 volume={10},
 url={https://api.semanticscholar.org/CorpusID:7275572}
}
It is demonstrated that KvS subunits modify the pharmacological response of Kv2 subunits when assembled in heterotetramers and illustrate the potential of K vS sub units to provide unique pharmacological properties to the heterotETramers, as is the case for 4−AP on Kv 2.1/Kv6.4 channels.

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62 References

The Electrically Silent Kv6.4 Subunit Confers Hyperpolarized Gating Charge Movement in Kv2.1/Kv6.4 Heterotetrameric Channels
The results provide a mechanistic basis for the modulation of Kv2.1/Kv6.4 channel inactivation gating kinetics by silent Kv 6.4 subunits and reveal a second sigmoidal relationship of the voltage-dependence of gating charge movement around the physiological K+ equilibrium potential.

Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes.
This work demonstrated that Kv8.2 G476D, analogous to a disease-causing human mutation, eliminated Kv2.1 current and suggested that the custom-tailored current of KV2.2 functionally contributes to photoreception, and this is the reason that mutations of Kv 8.2 lead to a genetic visual disorder.

Structural and functional characterization of Kv6.2 a new gamma-subunit of voltage-gated potassium channel.
The data suggest that delayed-rectifier type channels containing Kv6.2 subunits may contribute to cardiac action potential repolarization and is proposed that this protein protein interaction underlies Kv2.1/Kv 6.2 channels.

Gating Charge Immobilization in Kv4.2 Channels: The Basis of Closed-State Inactivation
Q-immobilization and closed-state inactivation at hyperpolarized voltages are two manifestations of the same process in Kv4.2 channels, and it is proposed that inactivation in the absence of N- and P/C-type mechanisms involves desensitization to voltage resulting from a slow conformational change of the voltage sensors, which renders the channel's main activation gate reluctant to open.

Gating-dependent mechanism of 4-aminopyridine block in two related potassium channels
Results indicate that in both channels 4AP enters the intracellular mouth to bind to a site that is guarded by the gating mechanism, which may be important for specifying the 4AP sensitivity in related voltage-gated K+ channels.

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.
This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells and concludes that Kv2.

Domain analysis of Kv6.3, an electrically silent channel
The silent behaviour of Kv6.3 is largely caused by the C‐terminal part of its sixth transmembrane domain that causes ER retention of the subunit, which could act as a voltage sensor in the Kv2.1 context.

Obligatory heterotetramerization of three previously uncharacterized Kv channel α-subunits identified in the human genome
Three unique α-subunits of voltage-gated K+ channel subunits in the human genome are identified, suggesting that obligatory heterotetramer formation is more widespread than previously thought.
...