Journal
EMBO JOURNAL
Volume 30, Issue 17, Pages 3607-3619Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2011.268
Keywords
channel gating; K plus channel; K2P channel; potassium channel; TREK-1
Categories
Funding
- Deutsche Forschungsgemeinschaft [BA 1793/5-1]
- Wellcome Trust
- Pfizer UK
- BBSRC [BB/H000267/1, BB/I019855/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I019855/1, BB/H000267/1, BBS/B/16011, B19456, BEP17032] Funding Source: researchfish
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Two-pore domain (K2P) potassium channels are important regulators of cellular electrical excitability. However, the structure of these channels and their gating mechanism, in particular the role of the bundle-crossing gate, are not well understood. Here, we report that quaternary ammonium (QA) ions bind with high-affinity deep within the pore of TREK-1 and have free access to their binding site before channel activation by intracellular pH or pressure. This demonstrates that, unlike most other K(+) channels, the bundle-crossing gate in this K2P channel is constitutively open. Furthermore, we used QA ions to probe the pore structure of TREK-1 by systematic scanning mutagenesis and comparison of these results with different possible structural models. This revealed that the TREK-1 pore most closely resembles the open-state structure of KvAP. We also found that mutations close to the selectivity filter and the nature of the permeant ion profoundly influence TREK-1 channel gating. These results demonstrate that the primary activation mechanisms in TREK-1 reside close to, or within the selectivity filter and do not involve gating at the cytoplasmic bundle crossing. The EMBO Journal (2011) 30, 3607-3619. doi:10.1038/emboj.2011.268; Published online 5 August 2011
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