Journal
SCIENCE
Volume 347, Issue 6227, Pages 1256-1259Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1261512
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Funding
- AbbVie [1097737]
- Bayer
- Boehringer Ingelheim
- Genome Canada through Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- UK Biotechnology and Biological Sciences Research Council
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/J00037X/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1104933] Funding Source: researchfish
- BBSRC [BB/J00037X/1] Funding Source: UKRI
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TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.
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