Article ; Online: Capturing distinct KCNQ2 channel resting states by metal ion bridges in the voltage-sensor domain.
The Journal of general physiology
2014 Volume 144, Issue 6, Page(s) 513–527
Abstract: Although crystal structures of various voltage-gated K(+) (Kv) and Na(+) channels have provided substantial information on the activated conformation of the voltage-sensing domain (VSD), the topology of the VSD in its resting conformation remains highly ... ...
| Abstract | Although crystal structures of various voltage-gated K(+) (Kv) and Na(+) channels have provided substantial information on the activated conformation of the voltage-sensing domain (VSD), the topology of the VSD in its resting conformation remains highly debated. Numerous studies have investigated the VSD resting state in the Kv Shaker channel; however, few studies have explored this issue in other Kv channels. Here, we investigated the VSD resting state of KCNQ2, a K(+) channel subunit belonging to the KCNQ (Kv7) subfamily of Kv channels. KCNQ2 can coassemble with the KCNQ3 subunit to mediate the IM current that regulates neuronal excitability. In humans, mutations in KCNQ2 are associated with benign neonatal forms of epilepsy or with severe epileptic encephalopathy. We introduced cysteine mutations into the S4 transmembrane segment of the KCNQ2 VSD and determined that external application of Cd(2+) profoundly reduced the current amplitude of S4 cysteine mutants S195C, R198C, and R201C. Based on reactivity with the externally accessible endogenous cysteine C106 in S1, we infer that each of the above S4 cysteine mutants forms Cd(2+) bridges to stabilize a channel closed state. Disulfide bonds and metal bridges constrain the S4 residues S195, R198, and R201 near C106 in S1 in the resting state, and experiments using concatenated tetrameric constructs indicate that this occurs within the same VSD. KCNQ2 structural models suggest that three distinct resting channel states have been captured by the formation of different S4-S1 Cd(2+) bridges. Collectively, this work reveals that residue C106 in S1 can be very close to several N-terminal S4 residues for stabilizing different KCNQ2 resting conformations. |
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| MeSH term(s) | Animals ; Cadmium/chemistry ; Cadmium/pharmacology ; Cell Membrane Permeability/drug effects ; Cell Membrane Permeability/physiology ; Cells, Cultured ; Female ; Humans ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; KCNQ2 Potassium Channel/chemistry ; KCNQ2 Potassium Channel/physiology ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Oocytes/physiology ; Protein Binding ; Structure-Activity Relationship ; Xenopus laevis |
| Chemical Substances | KCNQ2 Potassium Channel ; Cadmium (00BH33GNGH) |
| Language | English |
| Publishing date | 2014-12 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3118-5 |
| ISSN | 1540-7748 ; 0022-1295 |
| ISSN (online) | 1540-7748 |
| ISSN | 0022-1295 |
| DOI | 10.1085/jgp.201411221 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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