|
Title
|
|
|
|
KCNQ1 channels voltage dependence through a voltage-dependent binding of the S4-S5 linker to the pore domain
|
|
|
Author
|
|
|
|
|
|
|
Abstract
|
|
|
|
| Voltage-dependent potassium (Kv) channels are tetramers of six transmembrane domain (S1S6) proteins. Crystallographic data demonstrate that the tetrameric pore (S5S6) is surrounded by four voltage sensor domains (S1S4). One key question remains: how do voltage sensors (S4) regulate pore gating? Previous mutagenesis data obtained on the Kv channel KCNQ1 highlighted the critical role of specific residues in both the S4-S5 linker (S4S5L) and S6 C terminus (S6T). From these data, we hypothesized that S4S5L behaves like a ligand specifically interacting with S6T and stabilizing the closed state. To test this hypothesis, we designed plasmid-encoded peptides corresponding to portions of S4S5L and S6T of the voltage-gated potassium channel KCNQ1 and evaluated their effects on the channel activity in the presence and absence of the ancillary subunit KCNE1. We showed that S4S5L peptides inhibit KCNQ1, in a reversible and state-dependent manner. S4S5L peptides also inhibited a voltage-independent KCNQ1 mutant. This inhibition was competitively prevented by a peptide mimicking S6T, consistent with S4S5L binding to S6T. Val254 in S4S5L is known to contact Leu353 in S6T when the channel is closed, and mutations of these residues alter the coupling between the two regions. The same mutations introduced in peptides altered their effects, further confirming S4S5L binding to S6T. Our results suggest a mechanistic model in which S4S5L acts as a voltage-dependent ligand bound to its receptor on S6 at rest. This interaction locks the channel in a closed state. Upon plasma membrane depolarization, S4 pulls S4S5L away from S6T, allowing channel opening. |
|
|
|
Language
|
|
|
|
English
|
|
|
Source (journal)
|
|
|
|
Journal of biological chemistry. - Baltimore, Md
|
|
|
Publication
|
|
|
|
Baltimore, Md
:
2011
|
|
|
ISSN
|
|
|
|
0021-9258
[print]
1083-351X
[online]
|
|
|
DOI
|
|
|
|
10.1074/JBC.M110.146324
|
|
|
Volume/pages
|
|
|
|
286
:1
(2011)
, p. 707-716
|
|
|
ISI
|
|
|
|
000285782800070
|
|
|
Full text (Publisher's DOI)
|
|
|
|
|
|
|
Full text (publisher's version - intranet only)
|
|
|
|
|
|