The concerted contribution of the S4-S5 linker and the S6 segment to the modulation of a Kv channel by 1-alkanols
Bhattacharji, A; Kaplan, B; Harris, T; Qu, X; Germann, MW; Covarrubias, M
HERO ID
783525
Reference Type
Journal Article
Year
2006
Language
English
PMID
| HERO ID | 783525 |
|---|---|
| In Press | No |
| Year | 2006 |
| Title | The concerted contribution of the S4-S5 linker and the S6 segment to the modulation of a Kv channel by 1-alkanols |
| Authors | Bhattacharji, A; Kaplan, B; Harris, T; Qu, X; Germann, MW; Covarrubias, M |
| Journal | Molecular Pharmacology |
| Volume | 70 |
| Issue | 5 |
| Page Numbers | 1542-1554 |
| Abstract | Gating of voltage-gated K(+) channels (K(v) channels) depends on the electromechanical coupling between the voltage sensor and activation gate. The main activation gate of K(v) channels involves the COOH-terminal section of the S6 segment (S6-b) and the S4-S5 linker at the intracellular mouth of the pore. In this study, we have expanded our earlier work to probe the concerted contribution of these regions to the putative amphipathic 1-alkanol site in the Shaw2 K(+) channel. In the S4-S5 linker, we found a direct energetic correlation between alpha-helical propensity and the inhibition of the Shaw2 channel by 1-butanol. Spectroscopic structural analyses of the S4-S5 linker supported this correlation. Furthermore, the analysis of chimeric Shaw2 and K(v)3.4 channels that exchanged their corresponding S4-S5 linkers showed that the potentiation induced by 1-butanol depends on the combination of a single mutation in the S6 PVPV motif (PVAV) and the presence of the Shaw2 S4-S5 linker. Then, using tandem-heterodimer subunits, we determined that this potentiation also depends on the number of S4-S5 linkers and PVAV mutations in the K(v) channel tetramer. Consistent with the critical contribution of the Shaw2 S4-S5 linker, the equivalent PVAV mutation in certain mammalian K(v) channels with divergent S4-S5 linkers conferred weak potentiation by 1-butanol. Overall, these results suggest that 1-alkanol action in Shaw2 channels depends on interactions involving the S4-S5 linker and the S6-b segment. Therefore, we propose that amphiphilic general anesthetic agents such as 1-alkanols may modulate gating of the Shaw2 K(+) channel by an interaction with its activation gate. |
| Doi | 10.1124/mol.106.026187 |
| Pmid | 16887933 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Is Qa | No |