scholarly journals Cooperative subunit interactions mediate fast C-type inactivation of hERG1 K+channels

2014 ◽  
Vol 592 (20) ◽  
pp. 4465-4480 ◽  
Author(s):  
Wei Wu ◽  
Alison Gardner ◽  
Michael C. Sanguinetti
Keyword(s):  
Subunit Interactions ◽  
K Channels

scholarly journals Concerted all-or-none subunit interactions mediate slow deactivation of humanether-à-go-go-related gene K+channels.

2016 ◽  
Vol 291 (41) ◽  
pp. 21423-21423
Author(s):  
Steven J. Thomson ◽  
Angela Hansen ◽  
Michael C. Sanguinetti
Keyword(s):  
Related Gene ◽  
Subunit Interactions ◽  
K Channels

Subunit Interactions in the Assembly of Neuronal Kir3.0 Inwardly Rectifying K+Channels

1997 ◽  
Vol 9 (3) ◽  
pp. 194-206 ◽  
Author(s):  
Erhard Wischmeyer ◽  
Frank Döring ◽  
Elke Wischmeyer ◽  
Alexander Spauschus ◽  
Achim Thomzig ◽  
...  
Keyword(s):  
Subunit Interactions ◽  
K Channels ◽  
Inwardly Rectifying

scholarly journals Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Humanether-à-go-go-related Gene K+Channels

2014 ◽  
Vol 289 (34) ◽  
pp. 23428-23436 ◽  
Author(s):  
Steven J. Thomson ◽  
Angela Hansen ◽  
Michael C. Sanguinetti
Keyword(s):  
Related Gene ◽  
Subunit Interactions ◽  
K Channels

scholarly journals Cooperative subunit interactions in C-type inactivation of K channels

1995 ◽  
Vol 69 (6) ◽  
pp. 2449-2457 ◽  
Author(s):  
E.M. Ogielska ◽  
W.N. Zagotta ◽  
T. Hoshi ◽  
S.H. Heinemann ◽  
J. Haab ◽  
...  
Keyword(s):  
Subunit Interactions ◽  
K Channels

scholarly journals Stoichiometry of altered hERG1 channel gating by small molecule activators

2014 ◽  
Vol 143 (4) ◽  
pp. 499-512 ◽  
Author(s):  
Wei Wu ◽  
Frank B. Sachse ◽  
Alison Gardner ◽  
Michael C. Sanguinetti
Keyword(s):  
Binding Sites ◽  
Channel Gating ◽  
Variable Number ◽  
Selectivity Filter ◽  
Subunit Interactions ◽  
Open Probability ◽  
K Channels ◽  
Channel Current ◽  
Number Of Binding Sites ◽  
Herg1 Channel

Voltage-gated K+ channels are tetramers formed by coassembly of four identical or highly related subunits. All four subunits contribute to formation of the selectivity filter, the narrowest region of the channel pore which determines K+ selective conductance. In some K+ channels, the selectivity filter can undergo a conformational change to reduce K+ flux by a mechanism called C-type inactivation. In human ether-a-go-go–related gene 1 (hERG1) K+ channels, C-type inactivation is allosterically inhibited by ICA-105574, a substituted benzamide. PD-118057, a 2-(phenylamino) benzoic acid, alters selectivity filter gating to enhance open probability of channels. Both compounds bind to a hydrophobic pocket located between adjacent hERG1 subunits. Accordingly, a homotetrameric channel contains four identical activator binding sites. Here we determine the number of binding sites required for maximal drug effect and determine the role of subunit interactions in the modulation of hERG1 gating by these compounds. Concatenated tetramers were constructed to contain a variable number (zero to four) of wild-type and mutant hERG1 subunits, either L646E to inhibit PD-118057 binding or F557L to inhibit ICA-105574 binding. Enhancement of hERG1 channel current magnitude by PD-118057 and attenuated inactivation by ICA-105574 were mediated by cooperative subunit interactions. Maximal effects of the both compounds required the presence of all four binding sites. Understanding how hERG1 agonists allosterically modify channel gating may facilitate mechanism-based drug design of novel agents for treatment of long QT syndrome.

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