Dataset Information

Effect of tyrphostin AG879 on Kv 4.2 and Kv 4.3 potassium channels.

ABSTRACT:

Background and purpose

A-type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv 4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv 4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv 4.2 inhibitor from. In the present study we characterized the effect of AG879 on cloned Kv 4.2/Kv channel-interacting protein 2 (KChIP2) channels.

Experimental approach

To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK-293 cells transiently-transfected with Kv 4.2 cDNA using the Maxcyte transfection system. The effects of AG879 were further examined on CHO-K1 cells expressing Kv 4.2/KChIP2 channels using a whole-cell patch-clamp technique.

Key results

Tyrphostin AG879 selectively and dose-dependently inhibited Kv 4.2 and Kv 4.3 channels. In Kv 4.2/KChIP2 channels, AG879 induced prominent acceleration of the inactivation rate, use-dependent block and slowed the recovery from inactivation. AG879 induced a hyperpolarizing shift in the voltage-dependence of the steady-state inactivation of Kv 4.2 channels without apparent effect on the V1/2 of the voltage-dependent activation. The blocking effect of AG879 was enhanced as channel inactivation increased. Furthermore, AG879 significantly inhibited the A-type potassium currents in the cultured hippocampus neurons.

Conclusion and implications

AG879 was identified as a selective and potent inhibitor the Kv 4.2 channel. AG879 inhibited Kv 4.2 channels by preferentially interacting with the open state and further accelerating their inactivation.

SUBMITTER: Yu H

PROVIDER: S-EPMC4500372 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Publications

Effect of tyrphostin AG879 on Kv 4.2 and Kv 4.3 potassium channels.

Yu Haibo H Zou Beiyan B Wang Xiaoliang X Li Min M

British journal of pharmacology 20150424 13

<h4>Background and purpose</h4>A-type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv 4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv 4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv 4.2 inhibitor from. In the present study we characterized the effect of ...[more]

PMID: 25752739

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Project description:Kv channels form voltage-dependent potassium selective pores in the outer cell membrane and are composed out of four α-subunits, each having six membrane-spanning α-helices (S1-S6). The α-subunits tetramerize such that the S5-S6 pore domains co-assemble into a centrally located K(+) pore which is surrounded by four operational voltage-sensing domains (VSD) that are each formed by the S1-S4 segments. Consequently, each subunit is capable of responding to changes in membrane potential and dictates whether the pore should be conductive or not. K(+) permeation through the pore can be sealed off by two separate gates in series: (a) at the inner S6 bundle crossing (BC gate) and (b) at the level of the selectivity filter (SF gate) located at the extracellular entrance of the pore. Within the last years a general consensus emerged that a direct communication between the S4S5-linker and the bottom part of S6 (S6(c)) constitutes the coupling with the VSD thus making the BC gate the main voltage-controllable activation gate. While the BC gate listens to the VSD, the SF changes its conformation depending on the status of the BC gate. Through the eyes of an entering K(+) ion, the operation of the BC gate apparatus can be compared with the iris-like motion of the diaphragm from a camera whereby its diameter widens. Two main gating motions have been proposed to create this BC gate widening: (1) tilting of the helix whereby the S6 converts from a straight α-helix to a tilted one or (2) swiveling of the S6(c) whereby the S6 remains bent. Such motions require a flexible hinge that decouples the pre- and post-hinge segment. Roughly at the middle of the S6 there exists a highly conserved glycine residue and a tandem proline motif that seem to fulfill the role of a gating hinge which allows for tilting/swiveling/rotations of the post-hinge S6 segment. In this review we delineate our current view on the operation of the BC gate for controlling K(+) permeation in Kv channels.

Dataset Information

Effect of tyrphostin AG879 on Kv 4.2 and Kv 4.3 potassium channels.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Effect of tyrphostin AG879 on Kv 4.2 and Kv 4.3 potassium channels.

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