Dataset Information

Selective activation of vascular Kv 7.4/Kv 7.5 K+ channels by fasudil contributes to its vasorelaxant effect.

ABSTRACT: BACKGROUND AND PURPOSE:Kv 7 (Kv 7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests Kv 7.4/Kv 7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported Kv 7 openers have shown poor selectivity across these five subtypes. In this study, fasudil - a drug used for cerebral vasospasm - has been found to be a selective opener of Kv 7.4/Kv 7.5 channels. EXPERIMENTAL APPROACH:A perforated whole-cell patch technique was used to record the currents and membrane potential. Homology modelling and a docking technique were used to investigate the interaction between fasudil and the Kv 7.4 channel. An isometric tension recording technique was used to assess the vascular tension. KEY RESULTS:Fasudil selectively and potently enhanced Kv 7.4 and Kv 7.4/Kv 7.5 currents expressed in HEK293 cells, and shifted the voltage-dependent activation curve in a more negative direction. Fasudil did not affect either Kv 7.2 and Kv 7.2/Kv 7.3 currents expressed in HEK293 cells, the native neuronal M-type K+ currents, or the resting membrane potential in small rat dorsal root ganglia neurons. The Val248 in S5 and Ile308 in S6 segment of Kv 7.4 were critical for this activating effect of fasudil. Fasudil relaxed precontracted rat small arteries in a concentration-dependent fashion; this effect was antagonized by the Kv 7 channel blocker XE991. CONCLUSIONS AND IMPLICATIONS:These results suggest that fasudil is a selective Kv 7.4/Kv 7.5 channel opener and provide a new dimension for developing selective Kv 7 modulators and a new prospective for the use, action and mechanism of fasudil.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5120158 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Selective activation of vascular Kv 7.4/Kv 7.5 K+ channels by fasudil contributes to its vasorelaxant effect.

Zhang Xuan X An Hailong H Li Junwei J Zhang Yuanyuan Y Liu Yang Y Jia Zhanfeng Z Zhang Wei W Chu Li L Zhang Hailin H

British journal of pharmacology 20161101 24

<h4>Background and purpose</h4>Kv 7 (Kv 7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests Kv 7.4/Kv 7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported Kv 7 openers have shown poor selectivity across these five subtypes. In this study, fasudil - a drug used for cerebral vasospasm - has been found ...[more]

PMID: 27677924

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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

Selective activation of vascular Kv 7.4/Kv 7.5 K+ channels by fasudil contributes to its vasorelaxant effect.

Publications

Selective activation of vascular K<sub>v</sub> 7.4/K<sub>v</sub> 7.5 K<sup>+</sup> channels by fasudil contributes to its vasorelaxant effect.

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