Title
Modulation of closed-state inactivation in Kv2.1/Kv6.4 heterotetramers as mechanism for 4-AP induced potentiation Modulation of closed-state inactivation in Kv2.1/Kv6.4 heterotetramers as mechanism for 4-AP induced potentiation
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Subject
Physics
Biology
Human medicine
Engineering sciences. Technology
Source (journal)
PLoS ONE
Volume/pages
10(2015) :10 , 21 p.
ISSN
1932-6203
1932-6203
Article Reference
e0141349
Carrier
E-only publicatie
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
The voltage−gated K+ (Kv) channel subunits Kv2.1 and Kv2.2 are expressed in almost every tissue. The diversity of Kv2 current is increased by interacting with the electrically silent Kv (KvS) subunits Kv5−Kv6 and Kv8−Kv9, into functional heterotetrameric Kv2/KvS channels. These Kv2/KvS channels possess unique biophysical properties and display a more tissue-specific expression pattern, making them more desirable pharmacological and therapeutic targets. However, little is known about the pharmacological properties of these heterotetrameric complexes. We demonstrate that Kv5.1, Kv8.1 and Kv9.3 currents were inhibited differently by the channel blocker 4−aminopyridine (4−AP) compared to Kv2.1 homotetramers. In contrast, Kv6.4 currents were potentiated by 4−AP while displaying moderately increased affinities for the channel pore blockers quinidine and flecainide. We found that the 4−AP induced potentiation of Kv6.4 currents was caused by modulation of the Kv6.4−mediated closed−state inactivation: suppression by 4−AP of the Kv2.1/Kv6.4 closed−state inactivation recovered a population of Kv2.1/Kv6.4 channels that was inactivated at resting conditions, i.e. at a holding potential of −80 mV. This modulation also resulted in a slower initiation and faster recovery from closed−state inactivation. Using chimeric substitutions between Kv6.4 and Kv9.3 subunits, we demonstrated that the lower half of the S6 domain (S6c) plays a crucial role in the 4−AP induced potentiation. These results demonstrate that KvS subunits modify the pharmacological response of Kv2 subunits when assembled in heterotetramers and illustrate the potential of KvS subunits to provide unique pharmacological properties to the heterotetramers, as is the case for 4−AP on Kv2.1/Kv6.4 channels.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/2ac120/128996.pdf
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